Method of treating schizophrenia or schizophreniform disorder

ABSTRACT

Described herein are compositions which include digestive enzymes which are formulated to reduce one or more symptoms of a neuropsychiatric disorder. Also described herein is a method for treating an individual with a neuropsychiatric disorder using digestive enzymes and their derivatives to alleviate the symptoms of neuropsychiatric disorders. The method comprises administering to the individual an effective amount of digestive enzymes that are either naturally- or recombinantly-derived, or their derivatives, in an amount effective to reduce one or more symptoms of the neuropsychiatric disorder.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.16/281,908, filed Feb. 21, 2019, which is a continuation of U.S.application Ser. No. 15/265,415, filed Sep. 14, 2016, now U.S. Pat. No.10,279,016, which is a continuation of U.S. application Ser. No.14/612,604, filed Feb. 3, 2015, now U.S. Pat. No. 9,492,515, which is acontinuation of U.S. application Ser. No. 14/007,793, filed Dec. 27,2013, now U.S. Pat. No. 8,980,252, which is a § 371 U.S. National PhaseEntry of PCT/US12/34489, filed Apr. 20, 2012, which claims the benefitof U.S. Provisional Application No. 61/477,988, filed Apr. 21, 2011,which application is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Neuropsychiatric disorders are some of the most debilitating, sociallyisolating and economically draining of all illnesses. The manifestationsof neuropsychiatric disorders, often mistaken as willful or controllablebehaviors cause the illness to be misdiagnosed and thus poorly treated.Most treatments for neuropsychiatric disorders have severe anddevastating side effects. These side effects will often discourage thepatient from continuing treatment and are often the cause of relapse.

Psychotic disorders represent the most difficult of all neuropsychiatricdisorders to control. The invariate nature of the presentation ofsymptoms of these disorders, together with the side effects exhibited bymedications used to alleviate these symptoms, makes their treatmentdifficult.

The introduction of antipsychotic drugs in the 1950's heralded the“golden age” of psychopharmacology. Their development has been comparedto the discovery of antibiotics for infectious diseases. Conventional or“typical” antipsychotic drugs, typified by chlorpromazine andhaloperidol, have a proven track record in the treatment ofschizophrenia. However, the “typical” antipsychotics described belowhave substantial limitations. They are most effective against thepsychotic symptoms of the illness in its early stages, but their sideeffects are troubling and contribute significantly to non-compliance,which leads to relapse and re-hospitalization.

SUMMARY OF THE INVENTION

There is a growing belief among clinicians that the “atypical”antipsychotics are or should become first-line treatments inschizophrenia. However, the exact nature and extent of the clinicaladvantages of the atypical drugs are not known. Moreover, they may costten times as much as older “typical” antipsychotics. Although a varietyof claims of efficacy and safety have been made, they are often based oninsufficient evidence.

Among the reasons for this is traditional clinical trials have excludedmany patients with schizophrenia, including those who are substanceabusers, violent or uncooperative, making it difficult to generalize theresults of such studies to real world patients. For reasons of externalvalidity, treatment effectiveness studies have sought to use morerepresentative sampling techniques. However, even effectiveness studiesrarely have representative samples of providers and systems of care, orlarge enough samples to have sufficient power to examine the role ofexternal factors affecting treatment outcome.

There is a need for a new class of drugs to treat neuropsychiatricdisorders, with at least equal effectiveness, but with a severelyreduced side effect profile, which will enhance compliance and lowerco-morbid symptomatology.

Provided herein are compositions of digestive enzymes which are usefulin the prevention or treatment of one or more symptoms of aneuropsychiatric disorder. Also provided herein are compositions ofdigestive enzymes which are useful for use in the prevention ortreatment of one or more symptoms of schizophrenia. Treatment of aneuropsychiatric disorder (e.g., schizophrenia) encompasses stasis ofone or more symptoms (i.e., they do not worsen), as well as reduction(partial or complete) of one or more symptoms. In one embodiment, one ormore symptoms of such disorders are reduced in severity or duration byabout 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, orabout 100%. In another embodiment, one or more symptoms of suchdisorders are reduced in severity or duration by about 2-fold, about5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold,about 30-fold, about 35-fold, about 40-fold, about 45-fold, about50-fold, about 55-fold, about 60-fold, about 65-fold, about 70-fold,about 75-fold, about 80-fold, about 90-fold, about 95-fold, about100-fold, or more. Compositions may include not only one or moredigestive enzymes, but also one or more pharmaceutically acceptablecarriers, excipients, buffers, fillers, binders, stabilizers,surfactants, diluents, taste maskers, etc.

Provided herein is a method for using digestive enzymes and theirderivatives to alleviate one or more symptoms of neuropsychiatricdisorders. The method comprises administering to the individual one ormore digestive enzymes that are either naturally- orrecombinantly-derived, or their derivatives, in an amount effective toreduce the one or more symptoms of the neuropsychiatric disorder.Digestive enzymes generally comprise all proteases, amylases, andlipases, as well as other proteins secreted in a mammal that affect thedigestive process either directly or indirectly.

The disorders that present symptoms potentially suitable for alleviationaccording to the present method include, but are not limited to:adjustment disorders, addiction, Alzheimer's disease, anxiety disorders,bipolar disorder, cognitive disorders, dementias, dissociativedisorders, eating disorders, impulse-control disorders, mood disorders,sexual disorders, sleep disorders, psychotic disorders such asschizophrenic disorders, somatoform disorders, substance abuse disordersand personality disorders. In one embodiment, a schizophreniformdisorder (e.g., schizophrenia) is treated according to the methodsdescribed herein

In another aspect, this disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of an enzymepreparation, which comprises a core amount of pancreatic or digestiveenzymes effective for treating a subject susceptible to treatment by theenzymes, specifically those suffering with neuropsychiatric disorders.

In another aspect, this disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of an enzymepreparation, which comprises a core amount of pancreatic or digestiveenzymes effective for treating a subject susceptible to treatment by theenzymes, specifically those suffering with schizophrenia.

In another aspect, this disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of an enzymepreparation, which comprises a core amount of pancreatic or digestiveenzymes effective for treating a subject susceptible to treatment by theenzymes, specifically those suffering with psychosis.

In one aspect, provided herein is a method for treating an individualexhibiting one or more symptoms of a neuropsychiatric disorder, themethod comprising administering a therapeutically effective amount ofdigestive enzymes to the individual. In one embodiment, theneuropsychiatric disorder is a schizophreniform disorder, or a mildanxiety state.

In another embodiment, a symptom of the neuropsychiatric disorder may bea positive symptom, a negative symptom, a symptom of cognitiveimpairment, or a combination thereof. Positive symptoms are include, butare not limited to hallucinations, delusions, disorganized thought,disorganized speech (e.g., frequent derailment or incoherence), movementdisorders, bizarre behavior, and any combinations thereof. Negativesymptoms include, but are not limited to limited to loss of motivation,restricted range of emotional experience and expression, reduced hedoniccapacity, affective flattening, alogia, avolition, and any combinationsthereof. Symptoms of cognitive impairment include, but are not limitedto poor executive function, inability to use learned information,difficulty paying attention and/or focusing, and any combinationsthereof.

Digestive enzymes to be used in a composition described herein includeamylase, lipase, protease, and any combination thereof. In anotherembodiment, digestive enzymes to be used in such compositions mayfurther include chymotrypsin, trypsin, pancreatin, papain, and anycombination thereof. Digestive enzymes may be derived from a source suchas, for example, animal enzymes, plant enzymes, synthetic enzymes, andany combination thereof. In a one embodiment, the animal enzyme isderived from a mammal.

Digestive enzymes may be manufactured using any appropriate technologyincluding, but not limited to, enteric coating, lipid encapsulation,direct compression, dry granulation, wet granulation, and anycombination thereof. A preparation may be an oral dosage formulationsuch as, for example, pills, tablets, capsules, microcapsules,mini-capsules, time released capsules, mini-tabs, sprinkles, and anycombination thereof. In one embodiment digestive enzymes are provided asa pharmaceutical composition. In one embodiment the pharmaceuticalcomposition is in the form of encapsulated sprinkles. In one embodimentthe encapsulation is a lipid coating. In one embodiment the lipidcoating is a soy lipid coating.

Provided herein is a method is presented for treating a symptom of aneuropsychiatric disorder in an individual comprising administering aneffective amount of a composition comprising one or more digestiveenzymes to the individual. In one embodiment, the neuropsychiatricdisorder is schizophrenia, schizophreniform disorders, or mild anxietystates.

In one embodiment, the digestive enzyme is selected from the groupconsisting of amylase, lipase, protease, and any combination thereof. Inanother embodiment, the digestive enzyme is further selected from thegroup consisting of: chymotrypsin, trypsin, pancreatin, papain, and anycombination thereof. In yet another embodiment, the digestive enzymesare derived from a source selected from the group consisting of animalenzymes, plant enzymes, synthetic enzymes, and any combination thereof.In one embodiment the digestive enzymes are pancreatic digestiveenzymes. In one embodiment, the animal enzyme is derived from a mammal.In one embodiment the mammal is a pig. In one embodiment, digestiveenzymes are derived from a mammalian pancreas. In one embodiment thepancreas is a pig pancreas.

In one embodiment, the total amount of protease in a composition rangesfrom about 5,000 to about 1,500,000 U.S.P. units/dose. In anotherembodiment, the total amount of amylase in a composition ranges fromabout 1,000 to about 15,000,000 U.S.P. units/dose. In anotherembodiment, the total amount of lipase in a composition ranges fromabout 1,500 to about 282,000 U.S.P. units/dose. In one embodiment apharmaceutical composition comprises about 23,000 U.S.P. units/dose oflipase, about 144,000 U.S.P. units/dose of amylase and about 140,000U.S.P. units/dose of protease. In another embodiment a pharmaceuticalcomposition contains 23040 U.S.P. units/dose of lipase, about 144,000U.S.P. units/dose of amylase and about 140,400 U.S.P. units/dose ofprotease.

Provided herein are methods for preventing or treating one or moresymptoms of a neuropsychiatric disorder in an individual comprising,administering to said individual a composition comprising one or moredigestive enzymes, wherein one or more symptoms of said neuropsychiatricdisorder are partially or completely reduced. In one aspect, theneuropsychiatric disorder is a schizophreniform disorder such as, forexample, schizophrenia. Symptoms of schizophrenia that may be treatedwith such methods include, but are not limited to, positive symptoms,negative symptoms, cognitive impairment, and any combination thereof.Positive symptoms include, but are not limited to, hallucinations,delusions, disorganized thought, disorganized speech (e.g., frequentderailment or incoherence), movement disorders, bizarre behavior, andany combination thereof. Negative symptoms include, but are not limitedto, loss of motivation, restricted range of emotional experience andexpression, reduced hedonic capacity, affective flattening, alogia,avolition, and any combination thereof. Symptoms of cognitive impairmentinclude, but are not limited to, poor executive function, inability touse learned information, difficulty paying attention and/or focusing,and any combination thereof.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the disclosure are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present disclosure will be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles of the disclosure are utilized, andthe accompanying drawings.

FIG. 1. The Test Substances.

FIG. 2. Description of the Dosages.

FIG. 3. Description of the Enzyme Components.

FIG. 4. Distance Moved by ckr Mice Treated with CM100 in SpontaneousOpen Field Assays.

FIG. 5. Velocity of ckr Mice Treated with CM100 in Spontaneous OpenField Assays.

FIG. 6. Aripiprazole Dose Dependent Response in ckr Mice.

FIG. 7. Total distance moved in the 90 min recording of spontaneous openfield test on male B6 mice. Data plot as Mean±SEM. Pair-wise comparisonusing Student's t-test. α=0.05. *, p<0.05; **, p<0.01; ***, p<0.001;N.S., not significant.

FIG. 8. Velocity in the 90 min recording of spontaneous open field teston male B6 mice. Data plot as Mean±SEM. Pair-wise comparison usingStudent's t-test. α=0.05. *, p<0.05; **, p<0.01; ***, p<0.001; N.S., notsignificant.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are methods of treating disorders relating toneuropsychiatric disorders and methods of diagnosing the likelihood ofhaving or developing a neuropsychiatric disorder.

Antipsychotic drugs are divided into two categories: “typical”antipsychotics and the newer “atypical” antipsychotics. Typicalantipsychotics have been shunned in recent times due to their sideeffect profile which includes the production of extrapyramidal symptomssuch a facial tics, gait disturbances, proprioceptive difficulties,rigidity, persistent muscle spasms, shakiness, restlessness, jitterinessand uncharacteristic movements.

Examples of antipsychotic drugs which fall into the “typical” categoryare: chlorpromazine, fluphenazine, haloperidol, loxapine, mesoridazine,molindone, perphenazine, pimozide, prochlorperazine, thiothixene,thioridazine and trifluoperazine.

With the advent of atypical antipsychotic drugs and their potential forenhanced efficacy and safety, the risk/benefit profile of this drugclass has changed. Following the re-introduction of the first atypicalantipsychotic, clozapine, in 1990, several new atypical drugs havebecome available for clinical use and now comprise more than 50% of theantipsychotic drug market in the United States. These drugs includerisperidone (1994), olanzapine (1996) and quetiapine (1997).

Examples of “atypical” antipsychotic drugs are: aripiprazole, asenapine,clozapine, iloperidone, lurasidone, olanzapine, paliperidone,quetiapine, risperidone and ziprasidone among others.

Recent research has provided strong evidence of the efficacy ofatypicals in schizophrenia, and demonstrated that they greatly reducethe risk of extrapyramidal side effects, as well as reducing tardivedyskinesias. “Dyskinesias” are repetitive, uncontrollable andpurposeless movements of the body or face. “Tardive” refers to thosesymptoms that develop after long-term antipsychotic treatment (severalyears). Unlike early dyskinesia symptoms, tardive dyskinesias may becomepermanent even if the antipsychotic medication is stopped.

These “atypical” antipsychotics are not without their side effects.While they have largely replaced the older medications, atypicals arerather expensive and carry a significant risk of weight gain (sometimesextreme weight gain) and diabetes. However, they may be more effectivethan the “typical” antipsychotics for such conditions as schizophrenia,and other schizoaffective disorders as well as for multiple types ofdepression and other mental illnesses.

Although the antipsychotics were first developed for schizophrenia,antipsychotic drugs are now broadly used for other disorders, includingbehavioral signs and symptoms associated with Alzheimer's disease,dementias, depression, and are generally applied to the entire classesof neuropsychiatric disorders including: adjustment disorders, anxietydisorders, dissociative disorders, eating disorders, impulse-controldisorders, mood disorders, sexual disorders, sleep disorders, psychoticdisorders, sexual disorders, somatoform disorders, substance abusedisorders, and personality disorders. Despite their widespread use inthese conditions, the overall effectiveness and safety of these drugsremain unclear.

Neurological and Neuropsychiatric Disorders

In accordance with the present disclosure, a method is presented foralleviating symptoms of neurological disorders. In one embodiment, themethod comprises administering to an individual a digestive enzymeeither naturally or recombinantly derived, or their derivatives in anamount effective to reduce the symptoms of the neurological disorders.

There are over 300 neuropsychiatric disorders listed in the DSM-IV andthere is overlap among the different diagnoses. Neuropsychiatricdisorders are categorized according to their predominant features. Forexample, phobias, social anxiety and post-traumatic stress disorder allinclude anxiety as a main feature of the disorder. Schizophrenia andrelated disorders such as delusional disorder, brief psychotic disorder,schizoaffective disorder, schizophreniform disorder and shared psychoticdisorder (a disorder that is characterized by the individual's inabilityto determine real from unreal), share similar characteristics.

In one embodiment, the neurological disorders that present symptomspotentially suitable for alleviation according to the present methodinclude, but are not limited to the following disorders and categoriesof disorders: adjustment disorders, addiction, Alzheimer's disease,anxiety disorders, bipolar disorder, cognitive disorders, dementias,dissociative disorders, eating disorders, impulse-control disorders,mood disorders, sexual disorders, sleep disorders, psychotic disorderssuch as schizophrenic disorders (e.g., schizophrenia), somatoformdisorders, substance abuse disorders and personality disorders.

As used herein, a schizophreniform disorder refers to a psychoticdisorder characterized by distortions of reality and disturbances ofthought and language and withdrawal from social contact.

Examples of anxiety conditions which are treated using the method ofthis disclosure include but are not limited to anxiety disorders, panicdisorder, panic disorder with agoraphobia, panic disorder withoutagoraphobia, agoraphobia without history of panic disorders, socialphobia, simple phobia, obsessive compulsive disorder, post-traumaticstress disorder, generalized anxiety disorder, anxiety disorder-nototherwise specified (NOS), organic anxiety disorder, psychoactivesubstance anxiety disorder, separation anxiety disorder, avoidantdisorder of childhood or adolescence, and overanxious disorder.

Examples of neuropsychiatric conditions which are treated using themethod of this disclosure include, but are not limited to,schizophrenia, catatonic, subchronic; schizophrenia, catatonic, chronic;schizophrenia, catatonic, subchronic with acute exacerbation;schizophrenia, catatonic, chronic with acute exacerbation;schizophrenia, catatonic, in remission; schizophrenia, catatonic,unspecified; schizophrenia, disorganized, subchronic; schizophrenia,disorganized, chronic; schizophrenia, disorganized, subchronic withacute exacerbation; schizophrenia, disorganized, chronic with acuteexacerbation; schizophrenia, disorganized, in remission; schizophrenia,disorganized, unspecified schizophrenia, paranoid, subchronic;schizophrenia, paranoid, chronic; schizophrenia, paranoid, subchronicwith acute exacerbation; schizophrenia, paranoid, chronic with acuteexacerbation; schizophrenia, paranoid, in remission; schizophrenia,paranoid, unspecified; schizophrenia, undifferentiated, subchronic;schizophrenia, undifferentiated, chronic; schizophrenia,undifferentiated, subchronic with acute exacerbation; schizophrenia,undifferentiated, chronic with acute exacerbation; schizophrenia,undifferentiated, in remission; schizophrenia, undifferentiated,unspecified; schizophrenia, residual, subchronic; schizophrenia,residual, chronic; schizophrenia, residual, subchronic with acuteexacerbation; schizophrenia, residual, chronic with acute exacerbation;schizophrenia, residual, in remission; schizophrenia, residual,unspecified; delusional (paranoid) disorder; brief reactive psychosis;schizophreniform disorder; schizoaffective disorder; personalitydisorders, schizoid; and personality disorders, schizotypal. In oneembodiment, clinical features or symptoms of schizophrenia includepositive symptoms, which include but are not limited to psychosis,hallucinations, delusions, disorganized thought, disorganized speech(e.g., frequent derailment or incoherence), movement disorders, andbizarre behavior. Delusions include but are not limited to false beliefsthat significantly hinder a person's ability to function. For example,an individual may have the delusion that people are trying to hurt themwhen there is no evidence of this, or the individual having the delusionthat they are somebody else. Hallucinations include false perceptions.Hallucinations may be visual (e.g., seeing things that are not there),auditory (e.g., hearing things that are not there), olfactory (e.g.,smelling things that are not there), tactile (e.g., feeling sensationson the skin that are not there, such as the feeling of bugs crawling onthe skin), or gustatory. Auditory hallucinations and paranoia aboutothers reading their minds, or being able to be in their bodies areexamples of symptoms experienced by schizophrenics. These symptomsappear to express an excess or distortion of normal function. Psychosisas used herein generally refers to an abnormal condition of the mind,and is a term for a mental state that may be described as a “loss ofcontact with reality” that is observed, in some cases, in patients withschizophrenia. Psychosis is given to the more severe forms ofpsychiatric disorder, during which hallucinations and delusions andimpaired insight may occur.

In another embodiment, clinical features or symptoms of schizophreniainclude negative symptoms, which include but are not limited to loss ofmotivation, restricted range of emotional experience and expression,reduced hedonic capacity, affective flattening, alogia, and avolition.Negative symptoms such as “flat affect”, lack of enjoyment, restrictedcommunication and inability to follow through on planned activities,losing interest in everyday activities such as bathing, grooming, orgetting dressed; feeling out of touch with other people, family, orfriends; a lack of feeling or emotion (apathy); having little emotion orinappropriate feelings in certain situations; and having less ability toexperience pleasure may be experienced. These reflect symptoms thatappear to express a loss or diminution of normal function.

In yet another embodiment, clinical features or symptoms ofschizophrenia include one or more symptoms of cognitive impairment. Forexample, cognitive impairment symptoms include poor executive function,inability to use learned information, and difficulty paying attentionand/or focusing.

Individuals with neuropsychiatric disorders frequently exhibit one ormore characteristics of the particular disorder. Additionally, thesecharacteristics often overlap with symptoms of other disorders withinthe category of neurological disorders as well as other disorderscharacterized as mental illness such as, but not limited to, Alzheimer'sand bipolar disorder. The present disclosure contemplates that one ormore symptoms as well as a complete constellation of symptoms within oneindividual may be alleviated by the present method.

Recognition and determination of a reduction in symptoms of any and allof these disorders can be readily performed by those skilled in the art.One will recognize that these psychotic conditions are characterized byhallucinations, delusions or grossly disorganized behavior, whichindicates that the patient suffers from gross impairment in reality.

In another embodiment, a patient treated with such methods exhibits animprovement in one or more symptoms of at least about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95% or about 100% compared to apatient treated with a control substance.

A “patient” to be treated by a method described herein refers to anadult or a child. In one embodiment, a patient to be treated is a humanfrom about 2 and about 10 years of age, from about 11 to about 20 yearsof age, or from about 21 to about 30 years of age.

Diagnosis

The recognition of the symptoms of the neuropsychiatric disorder ordisorders present in an individual and determination that the presentmethod may alleviate said symptoms prior to, during, or after thepractice of this method is well within the purview of an individualordinarily skilled in the art, who can perform suitable clinical,diagnostic, and or observational or other techniques required.

The DSM IV Diagnostic Criteria for Schizophrenia is described below:

A. Characteristic symptoms: Two (or more) of the following, each presentfor a significant portion of time during a 1-month period (or less ifsuccessfully treated): delusions, hallucinations, disorganized speech(e.g., frequent derailment or incoherence), grossly disorganized orcatatonic behavior, negative symptoms, i.e., affective flattening,alogia, or avolition. Only one Criterion A symptom is required ifdelusions are bizarre or hallucinations consist of a voice keeping up arunning commentary on the person's behavior or thoughts, or two or morevoices conversing with each other.

B. Social/occupational dysfunction: For a significant portion of thetime since the onset of the disturbance, one or more major areas offunctioning such as work, interpersonal relations, or self-care aremarkedly below the level achieved prior to the onset (or when the onsetis in childhood or adolescence, failure to achieve expected level ofinterpersonal, academic, or occupational achievement).

C. Duration: Continuous signs of the disturbance persist for at least 6months. This 6-month period must include at least 1 month of symptoms(or less if successfully treated) that meet Criterion A (i.e.,active-phase symptoms) and may include periods of prodromal or residualsymptoms. During these prodromal or residual periods, the signs of thedisturbance may be manifested by only negative symptoms or two or moresymptoms listed in Criterion A present in an attenuated form (e.g., oddbeliefs, unusual perceptual experiences).

Compositions and Formulations

Digestive enzymes are produced by the salivary glands, glands in thestomach, the pancreas and glands in the small intestines. Digestiveenzymes produced by the pancreas are secreted into the duodenum, orupper segment of the small intestine, raising the pH to around 5 or 6,and they assist in the digestion of food components, includingcarbohydrates, lipids, proteins and nucleic acids.

Digestive enzymes have been administered to mammals to treat enzymedeficiencies caused by conditions affecting the pancreas, such aspancreatitis and pancreatic enzyme deficiency. Pancreatic enzymesadministered to humans are commonly of porcine origin. Individuals withcystic fibrosis require the administration of enzymes, particularlylipases, in the maintenance of their condition. Manufacturers of enzymepreparations for these individuals have used enteric coatings fortargeted delivery in the distal section of the small intestine, wherelipase activity is important.

In another aspect, this disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of an enzymepreparation, which comprises a core amount of pancreatic or digestiveenzymes effective for treating a subject susceptible to treatment by theenzymes, specifically those suffering with neuropsychiatric disorders.

In another aspect, this disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of an enzymepreparation, which comprises a core amount of pancreatic or digestiveenzymes effective for treating a subject susceptible to treatment by theenzymes, specifically those suffering with schizophrenia.

In another aspect, this disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of an enzymepreparation, which comprises a core amount of pancreatic or digestiveenzymes effective for treating a subject susceptible to treatment by theenzymes, specifically those suffering with psychosis.

In one embodiment of the present disclosure, digestive enzymes compriseproteases, amylases and lipases, as well as other proteins secreted in amammal that affect the digestive process either directly or indirectly.In one aspect, digestive enzymes present in the composition include anamylase, a protease, or a lipase.

In another aspect, digestive enzymes present in the composition includetwo or more of: an amylase, a protease, and a lipase.

In one aspect, digestive enzymes present in the composition include anamylase, a protease, and a lipase.

In another aspect, a composition may further contain one or more ofcellulase, papaya, bromelain, chymotrypsin, and trypsin.

In one embodiment, the digestive or pancreatic enzyme compositioncomprises one or more of the following: amylases, proteases, cellulase,papaya, bromelain, lipases, chymotrypsin, and trypsin.

Compositions may contain an amount of protease from about 5,000 to about1,500,000 U.S.P. units/dose including, but not limited to about 5,000;about 7,500; about 10,000; about 15,000; about 20,000; about 25,000;about 30,000; about 40,000; about 50,000; about 65,000; about 75,000;about 100,000; about 140,000; about 140,400; about 150,000; about200,000; about 250,000; about 300,000; about 350,000; about 400,000;about 450,000; about 465,000; about 500,000; about 550,000; about600,000; about 650,000; about 700,000; about 750,000; about 800,000;about 850,000; about 900,000; about 950,000; about 1,000,000; about1,050,000; about 1,100,000; about 1,150,000; about 1,200,000; about1,250,000; about 1,300,000; about 1,350,000; about 1,400,000; about1,450,000; or about 1,500,000; about 1,200,000; about 1,250,000; about1,300,000; about 1,350,000; about 1,400,000; about 1,450,000; and about1,500,000 U.S.P. units/dose along with all values in between per dose.

Compositions may contain an amount of amylase from about 1,000 to about15,000,000 U.S.P. units/dose including, but not limited to about 1,000;about 3,000; about 5,000; about 7,500; about 10,000; about 15,000; about20,000; about 25,000; about 30,000; about 40,000; about 50,000; about65,000; about 75,000; about 100,000; about 144,000; about 500,000; about1,000,000; about 2,000,000; about 3,000,000; about 4,000,000; about5,000,000; about 6,000,000; about 7,000,000; about 8,000,000; about9,000,000; about 10,000,000; about 11,000,000; about 12,000,000; about13,000,000; about 14,000,000; and about 15,000,000 U.S.P. units/dose,along with all values in-between per dose.

Compositions may contain an amount of lipase from about 1,500 to about282,000 U.S.P. units/dose including, but not limited to, about 1,500;about 1,880; about 2,000; about 3,000; about 5,000; about 7,500; about10,000; about 15,000; about 20,000; about 23,000; about 23,040; about25,000; about 30,000; about 40,000; about 50,000; about 65,000; about75,000; about 100,000; about 125,000; about 150,000; about 200,000;about 250,000; and about 282,000 U.S.P. units/dose along with all valuesin-between per dose.

In another embodiment, the digestive enzyme composition is comprised ofprotease, lipase, and amylase where the activities are: protease between10,000 to 1,500,000 U.S.P. units/dose including 10,000; 100,000;150,000; 200,000; 250,000; 300,000; 350,000; 400,000; 450,000; about465,000; 500,000; 550,000; 600,000; 650,000; 700,000; 750,000; 800,000;850,000; 900,000; 950,000; 1,000,000; 1,050,000; 1,100,000; 1,150,000;1,200,000; 1,250,000; 1,300,000; 1,350,000; 1,400,000; 1,450,000; and1,500,000 along with all values in between per dose and where the ratioof protease to lipase is such that the amount of lipase is never morethan 0.188 times the amount of protease and where the ratio of proteaseactivity to amylase activity is between 1:0.1 and 1:10.

In another embodiment a pharmaceutical composition comprises about23,000 U.S.P. units/dose of lipase, about 144,000 U.S.P. units/dose ofamylase and about 140,000 U.S.P. units/dose of protease. In anotherembodiment a pharmaceutical composition contains about 23,040 U.S.P.units/dose of lipase, about 144,000 U.S.P. units/dose of amylase andabout 140,400 U.S.P. units/dose of protease.

In some embodiments, the digestive enzyme composition comprises at leastone protease and at least one lipase, wherein the ratio of totalproteases to total lipases (in U.S.P. units) ranges from about 5.371:1to about 20:1 including 5.371:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11;1, 12;1,13;1, 14:1, 15:1, 16;1, 17:1, 18:1, 19:1 and 20:1, along with all valuesin-between. In some embodiments, the ratio of proteases to lipasesranges from about 5.371:1 to about 10:1 including 5.371:1, 6:1, 7:1,8:1, 9:1, and 10:1, along with all values in-between.

In yet another embodiment, the digestive enzyme composition comprises atleast one protease and at least one lipase, wherein the ratio of totalproteases to total lipases (in U.S.P. units/dose) ranges from about5.371:1 to about 20:1 including 5.371:1, 6:1, 7.1, 8.1, 9:1, 10:1, 11:1,12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, and 20:1, along with allvalues in-between. In another embodiment, the digestive enzymecomposition comprises at least one protease and at least one lipase,wherein the ratio of total proteases to total lipases (in U.S.P.units/dose) ranges from about 1:1 to about 20:1. In yet anotherembodiment, the ratio of proteases to lipases ranges from about 4:1 toabout 10:1. In one embodiment, the ratio of proteases to lipases rangesfrom about 5.371:1 to about 10:1 including 5.371:1, 6:1, 7:1, 8:1, 9:1,and 10:1 along with all values in-between. In one embodiment, thedigestive enzyme composition comprises at least one protease and atleast one amylase, wherein the ratio of total proteases to totalamylases (in U.S.P. units/dose) ranges from about 1:0.1 to about 1:10including 1:0.25, 1:0.5, 1:0.75, 1:1, 1:1.25, 1:1.5, 1:1.75: 1:2,1:1.25, 1:1.5, 1:1.75, 1:1.2, 1:1.25, 1:1.5, 1:1.75, 1:1.2, 1:1.25,1:1.5, 1:1.75, 1:1.2: 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1.9 and1:10 along with all values in-between.

The disclosure also relates to a specific blend of enzymes, with orwithout coating, with or without other components as described abovewhereby enzyme administration occurs in individuals with a neurologicalor neuropsychiatric disorder, including but not limited to: adjustmentdisorders, addiction, Alzheimer's disease, anxiety disorders, bipolardisorder, cognitive disorders, dementias, dissociative disorders, eatingdisorders, impulse-control disorders, mood disorders, sexual disorders,sleep disorders, psychotic disorders such as schizophrenic disorders(e.g., schizophrenia), somatoform disorders, substance abuse disordersand personality disorders. Recognition and determination of a reductionof symptoms of any and all of these disorders can be readily performedby those skilled in the art using conventional assays.

In one embodiment of the present disclosure, uncoated digestive enzymescomprise proteases, amylases and lipases, as well as other proteinssecreted in a mammal, which affect the digestive process either directlyor indirectly. In one embodiment, the digestive or pancreatic enzymecomposition comprises one or more of the following: amylases, proteases,cellulase, papaya, bromelain, lipases, chymotrypsin, and trypsin.

In one embodiment the coated or uncoated digestive enzymes to beadministered are comprised of pancreatin, pancrelipase, or a combinationthereof. In one embodiment a coating technology can be used, such as theones described in U.S. Pat. Nos. 6,835,397, 6,153,236, or US2009-0004285 which are herein incorporated by reference in theirentirety.

Enzyme preparations with non-lipid enteric coatings can be used todeliver lipases in individuals in need of lipase administration. Certainmethods and enzyme compositions for use in treating children and otherindividuals in, for example, U.S. Pat. Nos. 7,138,123, 6,660,831,6,632,429, 6,534,063, which is herein incorporated by reference in itsentirety.

The composition of the dosage form may include other components,generally utilized in pharmaceutical preparations including but notlimited to binders, disintegrants, extracts, lubricants, fillers,flavorings, preservatives, colorants, taste maskers, diluents andcoating agents, such as vegetable oil, crystalline oils, and othercoating methodologies.

In one embodiment, coating of a digestive enzyme preparation is used toobtain release at selected transit times or in selected locations of thegastrointestinal tract of humans. In one aspect, this disclosure relatesto controlled release enzyme preparations administered to an individualwith a neuropsychiatric disorder.

In yet another aspect, this disclosure relates to an enzyme deliverysystem comprising a coated enzyme preparation having particles whichcomprise: (a) a core comprising pancreatic or digestive enzymes presentin an amount from about 5% to 99% by weight of the particles; and (b) agenerally uniform coating to provide for controlled release of theenzymes, said coating comprising an emulsifiable lipid. In one aspect,the coated enzyme preparation particles of the enzyme delivery systemare non-aerosolizable.

In some embodiments a coated digestive enzyme preparation comprising (a)a core containing a digestive enzyme particle, where the enzyme presentin an amount of from about 5% to 95% by weight of the particles,including 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90% and 95% by weight, along with all valuesin-between; and (b) a coating comprising a crystallizable lipid, whereinthe coating continuously coats the core and the crystallizable lipidreleases the enzyme upon exposure to physiological conditions.

In some embodiments a coated enzyme preparation having particles whichcomprise: (a) a core comprising pancreatic or other digestive enzymespresent in an amount of from about 5% to 95% by weight of the particles,including 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90% and 95% by weight along with all valuesin-between; and (b) a generally uniform coating to provide forcontrolled release of the enzymes, the coating comprising acrystallizable lipid. In some embodiments, the coated enzyme preparationparticles of the enzyme delivery system are non-aerosolizable.

The present disclosure also relates to methods of making the enzymepreparations by lipid coating and/or encapsulation of digestive enzymes.The methods comprise providing an emulsifiable lipid, and coatingpancreatic/digestive enzyme particles with the lipid. The digestiveenzymes comprise 5 to 99% of the coated enzyme preparations by weight.

In another aspect as described herein, the inventors have discoveredthat the methods of this disclosure produce coated digestive enzymepreparations comprising digestive and/or pancreatic enzymes coated withan emulsifiable lipid alone, or with a lipid blend to achieve acontrolled rate of enzyme release, with increased release of thepancreatic/digestive enzyme upon exposure of the coated preparation to asuitable solvent. The inventors have discovered that coatedpancreatic/digestive enzyme preparations having a coating consistingessentially of one or more monoglycerides exhibit time-sensitivebiologically-suitable release of the pancreatic/digestive enzymes uponexposure of the coated composite to a solvent, such as water, whileprotecting against release in 0.1 N HCl or acidic gastric fluid.

The nature of the human digestive tract creates challenges for thedelivery of digestive enzymes to patients susceptible to treatment withdigestive enzymes. Multiple temperature and pH changes over the courseof the digestive tract make specific delivery a challenge but anecessity. For instance, pH as low as 1 is encountered in the stomach,but rapidly increases to a more basic pH of 5-6 in the proximal smallintestine. For example, generally the pH in the stomach is approximately1.2, the pH in the duodenum is about 5.0 to 6.0; the pH in the jejunumis about 6.8, and the pH is about 7.2 in the proximal ileum and about7.5 in the distal ileum. The low pH in the stomach that changes rapidlyto a more basic pH of 5-6 in the proximal small intestines calls for aspecific delivery method depending upon where the enzyme is to bedelivered.

Delivery of digestive enzymes can also be challenging due to the rapiddegradation and denaturing of enzymes at ambient room temperature, aswell as the enhanced degradation and denaturing that can occur with hightemperature, pressure, humidity and/or exposure to light. Moisture andheat together can quickly destabilize enzymes, reducing theireffectiveness, and weaken their potency leading to inaccurate dosing andshortened shelf life. Denaturation or destabilization of the enzymes canreduce their effectiveness by reducing the dose of active enzymes toless than the amount needed for effective treatment. In one embodiment,to protect and stabilize the pancreatic/digestive enzyme fromunfavorable conditions such as oxidation, the pancreatic/digestiveenzyme (core) is coated or encapsulated in a continuous coatingcontaining an emulsifiable lipid. In another aspect, this disclosureprovides new coated enzyme preparations with improved shelf life.

Manufacturers of enzyme preparations have used enteric coatings todeliver lipases in individuals requiring administration of lipases, suchas individuals with cystic fibrosis. Because the porcine enzymes aredelivered in a mixture of proteases, lipases and amylases, and becausethese compositions for human consumption were prepared for lipasedelivery, the uses of these enteric coatings, which include suchsubstances as hypromellose phthalate, dimethicone 1000, and dibutylphthalate, preclude delivery of proteases at the proper location forprotein digestion, which is the duodenum. All other enzyme preparationspresently on the market contain at least one of these enteric coatingsubstances and/or other additives in the preparation.

In one embodiment the present disclosure includes a coated digestiveenzyme preparation and/or composite, which in some embodiments is anencapsulated pancreatic/digestive enzyme preparation. In other aspects,the disclosure includes enzyme delivery systems and pharmaceuticalcompositions comprising coated pancreatic/digestive enzyme preparations.These coated or encapsulated enzyme preparations contain corescomprising pancreatic or digestive enzyme particles, and a coatingcomprising an emulsifiable lipid.

The coatings in the digestive/pancreatic enzyme preparations create abarrier to degradation and denaturation, and allow more accurate levelsof active enzymes to be utilized by treated individuals. The lipidcoating of this disclosure provides a significant barrier to moisture,humidity and exposure to light by allowing for a physical barrier aswell as one that prevents and/or reduces hydrolysis. The coated enzymepreparations undergo less hydrolysis as a result of protection frommoisture in the environment by the lipid coating. As a result of thepresent disclosure, pancreatic/digestive enzymes are provided which cantolerate storage conditions (e.g., moisture, heat, oxygen, etc.) forlong periods of time thus enabling extended shelf life. The coating ofthe encapsulated enzyme preparation protects the enzyme from theenvironment and provides emulsification in a solvent without detractingfrom the abrasion resistance of the coating. The disclosure thus furtherrelates to more stable enzyme preparations.

It is another aspect of the present disclosure to make an enzymepreparation without the use of extenders colorants, dyes, flow enhancersand other additives to reduce the potential for allergens and othersensitivity reactions in children and other treated individuals. It hasbeen discovered that in some embodiments, the digestive enzymes can beencapsulated with a single lipid excipient to improve retention ofenzyme activity, ease of administration, tolerability, and safety ofadministration, among other properties. Surprisingly, digestive enzymeparticles containing lipases can be successfully encapsulated withcoating consisting essentially of only hydrogenated soy oil.

Porcine pancreatic/digestive enzymes possess a significant odor andtaste, similar to cured or smoked pork. This taste and smell can bestrong and offensive to some individuals taking enzyme replacement, andespecially to children. In one embodiment, the addition of a lipidcoating provides significant odor and taste masking to the enzymepreparation, which allows for the tolerance of taste, as the lipidcoating is odorless and tasteless. The use of this method of tastemasking not involving the use of color, dyes, perfumes or othersubstances is preferable for the administration of medications, whichhave an unpleasant or undesirable taste and odor. In another embodiment,this disclosure relates to coated digestive enzyme preparations withimproved taste and odor.

In some embodiments, the coatings on the digestive enzyme particle coresare preferably continuous coatings. By “continuous”, it is meant thatthe pancreatic/digestive enzyme is completely surrounded. The continuouscoating fully surrounds or encapsulates the pancreatic/digestiveenzymes. The encapsulation provides protection of thepancreatic/digestive enzyme from conditions such as moisture andoxidation.

In the manufacture of pharmaceuticals, encapsulation refers to a rangeof techniques used to enclose medicines in a relatively stable shellknown as a capsule, allowing them to, for example, be taken orally or beused as suppositories. “Encapsulate” as used herein means that thecoating completely surrounds the pancreatic/digestive enzyme. A coatedor encapsulated preparation may contain one or more digestive enzymeparticles enveloped in one coating to form one coated or encapsulateddigestive enzyme particle in the coated or encapsulated digestive enzymepreparation.

The two main types of capsules are hard-shelled capsules, which arenormally used for dry, powdered ingredients, and soft-shelled capsules,primarily used for oils and for active ingredients that are dissolved orsuspended in oil. Both of these classes of capsule are made both fromgelatin and from plant-based gelling substances like carrageenans andmodified forms of starch and cellulose, and the latter form is usuallyseamless. Capsules are made in two parts by dipping metal rods in moltengelatin solution. The capsules are supplied as closed units to thepharmaceutical manufacturer. Before use, the two halves are separated,the capsule is filled with powder (either by placing a compressed slugof powder into one half of the capsule, or by filling one half of thecapsule with loose powder) and the other half of the capsule is pressedon. The advantage of inserting a slug of compressed powder is thatcontrol of weight variation is better, but the machinery involved ismore complex.

Sprinkle capsules are a dosage form consisting of small beads orgranules of an active drug contained in a capsule that can be readilyadministered by simply opening up the capsule and distributing thecontents over something to be swallowed.

In addition, the encapsulation also provides controlled release of thepancreatic/digestive enzyme. In one embodiment, the emulsificationproperties of the coating in a solvent allows for controlled release ofthe enzyme in the gastrointestinal (GI) system, preferably the region ofthe GI tract where the enzymes are to be utilized. For example, forconditions requiring treatment with proteases, the release of theprotease portion of the enzymes is necessary in the proximal smallintestine, thereby necessitating a lipid encapsulation, which has adissolution profile showing a release of between 10% to 100% of theactive substance into solution over a time period of between 30 and 90minutes. In one embodiment, the dissolution profile shows a release ofabout 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, and all values inbetween, of the coated substance into solution over a time period ofabout 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 minutes andall values in between. Dissolution profiles may be obtained usingmethods and conditions known to those of skill in the art. For example,dissolution profiles can be determined at various pHs, including pH 1,2, 3, 4, 5, 6, 7, 8, 9, 10 and all values in between.

The rate of release of the bioactive substance can also be controlled bythe addition of additives as described below. When the preparations areexposed to a solvent, the solvent interacts with the mollifiable lipidin the coating and results in emulsification of the coating and releaseof the bioactive substance.

A suspension is a heterogeneous fluid containing solid particles thatare sufficiently large for sedimentation. Usually they must be largerthan 1 micrometer. The internal phase (solid) is dispersed throughoutthe external phase (fluid) through mechanical agitation, with the use ofcertain excipients or suspending agents. Unlike colloids, suspensionswill eventually settle. An example of a suspension would be sand inwater. The suspended particles are visible under a microscope and willsettle over time if left undisturbed. This distinguishes a suspensionfrom a colloid in which the suspended particles are smaller and do notsettle. Colloids and suspensions are different from a solution, in whichthe dissolved substance (solute) does not exist as a solid and solventand solute are homogeneously mixed. Oftentimes, powders of activeingredients may be packaged such that the addition of a diluentdissolves the powder and holds it in a liquid suspension.

A pharmaceutical preparation may be prepared in which an excipientprovides a matrix to capture and protect a product before delivery.Pharmaceutical preparations may be prepared whereby the individual whotakes the preparation has a reduction in the number of capsules/tabletsper dosage; i.e., the preparation is stabilized and may contain atherapeutically effective amount of a protease, an amylase, and/or alipase. Preparations may include, for example, a stabilizing matrixconsisting essentially of a solidified microcrystalline cellulose whichcaptures and protects therapeutically effective amounts of digestiveenzyme particles within the stabilizing matrix. This can be done, forexample, through the use of what is known in the art as PROSOLV®technology.

PROSOLV® is a combination of excipients which allow for optimized flow,compaction and product uniformity. This technology allows for uniformityin this combination, as well as manufacturing a very small tablet whichwould be amenable for children. With PROSOLV® technology, theingredients are not just blended, but are co-processed, which assuresthat equal particles are uniformly distributed and these results areeasily reproducible. This allows for stability and superb productquality.

Whether utilizing the PROSOLV® method or other methodology, the one ormore digestive enzymes will be formulated and manufactured such that theparticles will be uniformly distributed and there will be no overagewith respect to the amount of enzyme found in the preparation. Said newdrug formulation can be found in, but is not limited to, formulationswhich include digestive/pancreatic enzymes with and without theutilization of the PROSOLV® technology.

In a further embodiment, a direct compression method may be used for themanufacture of a pharmaceutical tablet preparation including the stepsof: (a) forming an active blend by blending an intimate admixture ofsilicified microcrystalline cellulose and a therapeutic agent comprisingone or more digestive enzymes; (b) forming a color blend by blending anintimate admixture of one or more pharmaceutically acceptable dyes andsilicified microcrystalline cellulose if color is necessary; (c)combining the active blend, the color blend and a disintegrant into apre-blend; (d) adding a lubricant to the pre-blend to form a finalblend; and (e) compressing the final blend to form a pharmaceuticaltablet preparation or a mixture of time released microtabs or a timereleased tablet.

This may be accomplished by combining the digestive enzymes with one ofthe patented PROSOLV® technologies, i.e.: PROSOLV® SMCC 50 or PROSOLV®SMCC 90, or other PROSOLV® technologies. When employing the PROSOLV®method, the silicified microcrystalline cellulose (SMCC) used in thepreparation of the present invention may be any commercially availablecombination of microcrystalline cellulose granulated with colloidalsilicon dioxide. The SMCC generally will be as described in Sherwood etal, Pharm. Tech., October 1998, 78-88 and U.S. Pat. No. 5,585,115, whichis incorporated herein by reference in its entirety. SMCC can beobtained commercially from Edward Mendell Company, Inc., a subsidiary ofPenwest Ltd., under the name PROSOLV® SMCC. There are different gradesof SMCC available, with particle size being the differentiating propertyamong the grades. For example, PROSOLV® SMCC 90 has a median particlesize, by sieve analysis, in the region of 90 micrometers. PROSOLV® SMCC50 has a median particle size, by sieve analysis, in the region of about40-50 micrometers.

A pharmaceutical composition described herein may be prepared using adirect compression method, a dry granulation method, or by wetgranulation. Preferably, the digestive/pancreatic enzyme preparation maybe prepared using a direct compression process. This preferred processconsists of two main steps: blending and compression.

The blending step is composed of an active blend, color blend,pre-blend, and final blend (lubrication). The formulation of the presentinvention may include a number of other ingredients for optimalcharacteristics of the pharmaceutical composition. Such otheringredients and the amounts to be used are within the knowledge of onein the art and are known in the pharmaceutical arts. These may includedisintegrates, lubricants and/or coloring agents among others. Suitabledisintegrants include, for example, sodium starch glycolate, otherstarches such as pregelatinized starch, and celluloses. Suitablelubricants may be provided, such as magnesium stearate, calciumstearate, talc and stearic acid. Any coloring agent certified by the FDAmay be used, such as FD&C Yellow #6, among others.

When used as a pharmaceutical preparation, elixirs contain an activeingredient that is dissolved in a solution that contains some percentage(usually 40-60%) of ethyl alcohol and is designed to be taken orally.

Syrups are oftentimes employed as a base for medicinal purposes andconsist of a concentrated or saturated solution of refined sugar indistilled water.

A suspension of liquid droplets or fine solid particles in a gas iscalled an aerosol. This can take the form of an oral spray.

A gum may be devised whereby an active ingredient is incorporated into avegetative resinous substance (e.g., acacia) and released via the actualmechanical effect of chewing or the action of saliva on the gum itself.

A thinstrip is an active pharmaceutical product coated by a lipid layerdesigned to dissolve in the mouth over a brief period of time. The sametechnology could be used to produce a medicated lollipop fortransmucosal delivery.

In pharmaceutical terms, a granule is a small particle gathered into alarger, permanent aggregate in which the original particles can still beidentified.

In some aspects, the disclosure relates to the production of selectedcoated enzyme preparations made by coating digestive enzyme particleswith lipids not previously used in coated digestive enzyme preparations.The unique mixtures of emulsifiable lipids and enzymes can delivercertain components of the pancreatic/digestive enzymes to selectedlocations and/or at selected times during transit of the GI tract. Insome aspects, the disclosure relates to methods of delivering digestiveenzymes to humans based upon dissolution profiles.

The emulsifiable lipid may be any lipid, lipid mixture, or blend oflipid and emulsifiers which emulsifies when exposed to a solvent, andhas a melting point which allows the lipid to be a solid at typicalstorage temperatures. The emulsifiable lipid can be a vegetable oranimal derived-lipid. In another embodiment, the emulsifiable lipidconsists essentially of, or comprises one or more monoglycerides,diglycerides or triglycerides, or other components including, forexample, emulsifiers found in hydrogenated vegetable oils. In anotherembodiment the lipid is a non-polar lipid.

As used herein, animal and/or vegetable “derived” lipids can includefats and oils originating from plant or animal sources and/or tissues,and/or synthetically produced based on the structures of fats and oilsoriginating from plant or animal sources. Lipid material may be refined,extracted or purified by known chemical or mechanical processes. Thelipid may, in one embodiment, comprise a Type I USP-National Formularyvegetable oil.

The digestive enzyme used in the present disclosure can be anycombination of digestive enzymes of a type produced by the pancreas,including, but not limited to digestive enzymes from a pancreatic sourceor other sources. The scope of the disclosure is not limited topancreatic enzymes of porcine origin, but can be of other animal orplant origin as well as those that are synthetically derived. In oneembodiment, the digestive enzyme is derived from mammalian sources suchas porcine-derived digestive enzymes. In another embodiment, the enzymeincludes one or more enzymes, and is plant derived, syntheticallyderived, recombinantly produced in microbial, yeast, or mammalian cells,or includes a mixture of enzymes from one or more sources. For example,digestive enzymes may include one or more enzymes from one or moresources mixed together. This includes, for example, the addition ofsingle digestive enzymes to digestive enzymes derived from pancreaticsources in order to provide appropriate levels of specific enzymes thatprovide more effective treatment for a selected disease or condition.One source of digestive enzymes can be obtained, for example, fromScientific Protein Laboratories. In one embodiment, the digestive enzymeis, for example a pancreatin/pancrelipase composition. In anotherembodiment, the digestive enzymes comprise or consist essentially of 25U.S.P. units protease, 2 U.S.P. units lipase, and 25 U.S.P. unitsamylase per milligram. The term digestive enzyme may refer to one ormore enzymes of a type produced by the pancreas.

In one embodiment, the digestive enzyme used present as consisting ofparticles having various sizes. In another embodiment, the particles ofdigestive enzyme are screened to obtain particles of a suitable size forencapsulation by removing particles that are too fine or too large. Forexample, the particles may be sieved to obtain particles of a suitablesize or more uniform size range for encapsulation.

In one embodiment, the minimum amount of pancreatic enzyme present inthe core is at least about 5% active enzymes by weight of the coatedenzyme preparation, but in another embodiment is at least about 30%, orat least about 50% by weight. In one embodiment, the maximum amount ofpancreatic/digestive enzyme present in the composite is at most about99% by weight, and in another embodiment is at most about 98%, 95%, 90%,85%, 80%, 75% or 70% of the coated enzyme preparation. In anotherembodiment, the amount of pancreatic enzyme present in the composite isabout 10%, 15%, 20%, 25%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 72.5%, 75%,77.5%, 80%, 82.5%, 87.5%, or 92.5% by weight or anywhere in between. Atleast about or at most about a % of enzyme may include equal to or aboutthat % of enzyme. The term “about” includes equal to, and a range thattakes into account experimental error in a given measurement. As used inconnection with particle sizes, the term “about” can refer to plus orminus 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% or anywhere in between. As usedin connection with % particles that can be sieved, the term “about” canrefer to plus or minus 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% or anywhere inbetween.

In one embodiment, the composition which contains the encapsulateddigestive enzyme preparation or composite is delivered as a sprinkle,powder, capsule, tablet, pellet, caplet or other oral form. In anotherembodiment, packaging the encapsulated enzyme preparations in an enzymedelivery system that further comprises single dose sachet-housedsprinkle preparations allows for ease of delivery and accurate dosing ofthe enzyme by allowing a specific amount of enzyme to be delivered ineach dosing. Allowing for specific unit dosing of an enzyme preparationwhich maintains the enzyme activity within specific stability parametersis an enhancement over other sprinkle formulations, which are housed ina multi-unit dosing form that allows for air, moisture and heat todepredate and denature the enzyme preparation. In one embodiment, thepowder or sachet is housed in a trilaminar pouch of which one layer isfoil, or similar barrier to keep out moisture and to protect the enzymepreparation from adverse environmental factors. The disclosure furtherrelates to an improvement in stability due to a reduction in hydrolysisdue to the lipid encapsulation and composition of package.

In another embodiment, the lipid encapsulation methodology reduces theaerosolization of the enzyme preparation that may be caustic to thepatient if inhaled. In another embodiment, the disclosure includesdelivery of digestive enzymes with improved safety of administration, byreducing the amount of aerosolization of the enzyme. The lipidencapsulation reduces aerosolization and the potential for caustic burn,aspiration, and/or aspiration pneumonias in patients and administratorsof the enzyme preparation, thereby reducing the potential for illness inalready compromised children such as those with cystic fibrosis, andleading to safer administration.

As used herein, the term “non-aerosolizable” will be used to refer to acoated or encapsulated enzyme preparation where substantially all of theparticles are large enough to eliminate or reduce aerosolization uponpouring of the coated enzyme preparation compared to uncoated enzymeparticles.

As described and referred to herein, suitable pancreatic/digestiveenzymes and suitable coatings may be used in the compositions andmethods of this disclosure. The choice of suitable enzymes and ofsuitable lipid coatings, including choice of the type or amount ofenzymes or coating, are guided by the specific enzyme needs of theindividuals, and the selected diseases to be treated. The encapsulatedenzyme preparations that are one aspect of this disclosure have not beenpreviously described.

In another embodiment, the disclosure relates to a method of controllingthe rate of release of the pancreatic/digestive enzyme from anencapsulated enzyme preparation upon exposure to a solvent. In oneaspect, the method comprises blending an emulsifiable lipid with anamount of one or more additives to obtain a lipid blend and coating thedigestive enzyme particle with the blend to form an encapsulateddigestive enzyme preparation containing particles comprising a corewhich contains the enzyme, and a coating which contains the lipid. Inone embodiment, the emulsifiable lipid is a blend where the emulsifiablelipid and additive are not the same, and where the rate of release ofthe enzyme from the encapsulated composite upon exposure to a solvent isdecreased as the amount of additive is increased. In the alternative,the rate of release of the enzyme from the encapsulated composite uponexposure to a solvent is increased as the amount of additive isdecreased.

The lipid coating surprisingly does not appear to be reduced ordestroyed by hydrochloric acid (HCl) present in the stomach, therebyprotecting the enzyme from degradation following administration untilthe enzyme preparation reaches its target region in the GI tract.Further the lipid coat reduces the exposure of the enzyme to attack bywater, thereby reducing hydrolysis, and further protecting the digestiveenzymes from degradation. In addition, the inventors have found that anexcipient containing only lipid can be used to coat or encapsulatedigestive enzyme particles containing lipase.

Enzyme preparations supplied by the API supplier may be provided asirregular shaped, and multi-sized particles, with uneven edges, and muchclumping, and containing some crystalline salt particles. Unevenparticle size and shape reduces flow properties, and interferes withpackaging. In addition, pouring uncoated enzyme into the mouth of anindividual would be difficult, and potentially may cause too much or toolittle of the enzyme to be delivered. In one embodiment, processing thedigestive enzyme particles according to methods in accordance with oneaspect of this disclosure yields a non-dusty, free-flowing particulatepreparation suitable for sachet packaging and for pouring onto food ordrink. In addition, as discussed throughout, the use of lipidencapsulation to prevent aerosolization and, therefore, increase safety,and to increase flow properties which enhance manufacturing of apharmaceutical is an embodiment of the instant disclosure.

“Emulsifiable lipids” as used herein means those lipids that contain atleast one hydrophilic group and at least one hydrophobic group, and havea structure capable of forming a hydrophilic and hydrophobic interface.These chemical and/or physical properties, mentioned above of anemulsifiable lipid permit emulsification. Examples of interfacesinclude, for example, micelles and bilayers. The hydrophilic group canbe a polar group and can be charged or uncharged.

In one embodiment, the emulsifiable lipid is derived from animal orvegetable origins, such as, for example, palm kernel oil, soybean oil,cottonseed oil, canola oil, and poultry fat, including hydrogenated typeI vegetable oils. In one embodiment, the lipid is hydrogenated. Inanother embodiment, the lipid is saturated or partially saturated.Examples of emulsifiable lipids include, but are not limited to,monoglycerides, diglycerides, fatty acids, esters of fatty acids,phospholipids, salts thereof, and combinations thereof.

The emulsifiable lipid is preferably a food grade emulsifiable lipid.Some examples of food grade emulsifiable lipids include sorbitanmonostearates, sorbitan tristearates and calcium stearoyl lactylates.Examples of food grade fatty acid esters which are emulsifiable lipidsinclude acetic acid esters of mono- and diglycerides, citric acid estersof mono- and di-glycerides, lactic acid esters of mono- anddigylcerides, polyglycerol esters of fatty acids, propylene glycolesters of fatty acids, and diacetyl tartaric acid esters of mono- anddiglycerides. Lipids can include, for example, hydrogenated soy oil. Anyemulsifiable lipid may be used in the methods and products of thisdisclosure. In one embodiment, the emulsifiable lipid used will producenon-agglomerating, non-aerosolizing enzyme preparation particles.

In another embodiment, the method relates to preparation of anencapsulated, controlled release digestive enzyme preparation withenhanced flow properties useful in the treatment of individuals with aneurological or neuropsychiatric disorder, the method comprising: a)blending an emulsifiable lipid with one or more additives to obtain ablend; and b) coating screened digestive enzyme with the blend to forman encapsulated digestive enzyme containing a core which contains thedigestive enzyme and a coating which contains the blend of emulsifiablelipid.

The coating of the enzyme with the lipid allows for the enzyme to becomemore uniform in size and shape, but reduces the jagged edges associatedwith the raw enzyme, and allows for ease of administration and ease ofpackaging, as the flow properties associated with the covered enzymewill allow for the packaging machinery to easily fill the sachet/pouchwith the enzyme and reduces overfilling or underfilling of the sachet.

In another embodiment, the disclosure relates to a method of controllingthe rate of release of a digestive enzyme from the encapsulatedpreparation by using a lipid blend to coat the digestive enzyme. Themethod includes blending an emulsifiable lipid with one or moreadditives to obtain a blend, and coating the digestive enzyme with theblend to form an encapsulated digestive enzyme containing a core whichcontains the digestive enzyme and a coating which contains the blend ofemulsifiable lipid. The rate of release of the enzyme from theencapsulated preparation upon exposure with a solvent is decreased asthe amount of additive is increased. In the alternative, the rate ofrelease of the enzyme from the encapsulated composite upon exposure witha solvent is increased as the amount of additive is decreased. Thus, thenature of the coating allows for controlled release of the enzyme fromthe encapsulate.

Different dosage forms have different benefits. Tablets and capsules arethe most common dosage forms for oral administration due to ease ofmanufacture, packaging and administration. Different forms of tabletshave been primarily devised to meet the needs of select populationswhile maintaining the integrity of the active pharmaceutical ingredient.Some populations, notably infants and young children, cannot swallowtablets or capsules or find it difficult to do so. In these instances, atablet that dissolves under the tongue, in the mouth, or in a specifiedliquid, or one that could be harmlessly chewed would be beneficial.Capsules that could be opened and their contents sprinkled over a smallamount of food or in a liquid would also be beneficial. Any improvementthat eases the administration of a necessary medication or lessens theantagonism associated with said administration, without compromising theeffectiveness of the active pharmaceutical ingredient, is worthwhile.

Other types of solid dosage forms such as thin strips, lollipops or gumbring a novel concept to the administration of medications to children.Aside from the obvious ease of administration from the viewpoint of thecaregiver, there may be an added benefit. The administration ofmedication is oftentimes a private issue and the ability of a caregiverto provide a dose of medication in a seemingly matter-of-fact form maypreserve that perception and instill in the user a mindset that viewsthe administration as pleasant rather than monotonous or negative.

Liquid dosage forms also provide benefits of administration to infantsand young children or anyone with compromised swallowing capability.Syrups, solutions and suspensions are easily swallowed. Unpleasanttastes can be masked by flavoring. An oral spray allows for the quickadministration of a pre-measured dose of medication and suppliesmultiple metered doses in one handy device. With no need to aidswallowing (such as a glass of water, etc.) and the convenience of nothaving to rifle through a bottle of tablets, administration issimplified.

A tablet is a mixture of active substances and excipients, usually inpowder form, pressed or compacted into a solid. The excipients includebinders, glidants (flow aids) and lubricants to ensure efficienttableting; disintegrants to ensure that the tablet breaks up in thedigestive tract; sweeteners or flavors to mask the taste of bad-tastingactive ingredients; and pigments to make uncoated tablets visuallyattractive. A coating (sugar, enteric or film) may be applied to hidethe taste of the tablet's components, to make the tablet smoother andeasier to swallow, and to make it more resistant to the environment,extending its shelf life. Tablets may be buffered (by potassiummetaphosphate, potassium phosphate, monobasic sodium acetate, etc.) tocombat change in pH. Tablets may be delayed-release, sustained-release,extended-release, controlled-delivery, long-acting,orally-disintegrating or melts, among others, often denoting thepharmacokinetic profile of the active agent. A capsule-shaped tablet isa caplet.

Some tablets may be taken sublingually or allowed to dissolve in themouth. The principle behind sublingual administration is simple. When achemical comes in contact with the mucous membrane beneath the tongue,or buccal mucosa, it diffuses through it. Because the connective tissuebeneath the epithelium contains a profusion of capillaries, thesubstance then diffuses into them and enters the venous circulation.Troches are medicated lozenges designed to dissolve in the mouth.Soluble tablets dissolve on contact with the tongue.

Slurry may be made when a dissolvable tablet containing a gelling agentis added to a liquid.

Tablets may also be micro-coated and placed in a capsule foradministration.

The compositions described herein can be administered either alone ormore typically in combination with one or more of a conventionalpharmaceutical carrier, excipient buffer, stabilizer or the like. Suchmaterials should be non-toxic and should not interfere with the efficacyof the active ingredient. The precise nature of the carrier or othermaterial will depend on the route of administration. The term“excipient” is used herein to describe any ingredient other than thecompound(s) (enzymes) used in the composition as described herein andknown in the art.

Acceptable carriers are physiologically acceptable to the administeredpatient and retain the therapeutic properties of the compounds with/inwhich it is administered. Acceptable carriers and their formulations areand generally described in, for example, Remington' pharmaceuticalSciences (18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa.1990). Two exemplary carriers are water and physiological saline. Thephrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the subject compoundsfrom the administration site to a portion of the body. Each carrier isacceptable in the sense of being compatible with the other ingredientsof the formulation and not injurious to a subject to whom it isadministered. Nor should an acceptable carrier alter the specificactivity of the subject compounds.

Acceptable carriers, excipients, or stabilizers are those that arenon-toxic to recipients at the dosages and concentrations employed, andinclude buffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid and methionine; preservatives (suchas octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides, and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; and/or non-ionic surfactants such as TWEEN®, PLURONICS® orpolyethylene glycol (PEG).

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that are physiologically tolerable and do not typicallyproduce an allergic or similar untoward reaction, such as gastric upset,dizziness and the like, when administered to a human.

Dosing, Administration and Methods

Methods of preparing such dosage forms are known, or will be apparent,to those skilled in this art; for example, see Remington: The Scienceand Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins.2005). Appropriate dosages will depend on the patient (age, weight,overall health, etc.), the severity of the condition, the type offormulation and other factors known to those having ordinary skill inthe art. It is to be noted that concentrations and dosage values canvary with the severity of the condition. It is to be further understoodthat for any particular patient, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the compositions.

In one embodiment a composition can be administered 1 or more times aday, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day with orwithout food. In another embodiment, a composition can be administeredorally 3 times a day with or without food.

The term “unit dose” when used in reference to a therapeutic compositionrefers to physically discrete units suitable as unitary dosage forhumans, each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect in association withthe required diluent; i.e., carrier, or vehicle.

Provided herein are methods for administering the enzymecompositions/preparations. In one aspect, the methods includeadministering the pancreatic/digestive enzymes as coated preparations.In another aspect, the disclosure relates to a method of treatmentcomprising administering to a subject with a neurological orneuropsychiatric disorder, including but not limited to: adjustmentdisorders, addiction, Alzheimer's disease, anxiety disorders, bipolardisorder, cognitive disorders, dementias, dissociative disorders, eatingdisorders, impulse-control disorders, mood disorders, sexual disorders,sleep disorders, psychotic disorders such as schizophrenic disorders(e.g., schizophrenia), somatoform disorders, substance abuse disordersand personality disorders, or other behavioral or neurological conditionin need of treatment with digestive enzymes, at least two doses of acomposition comprising a therapeutically effective amount of a coated oruncoated digestive enzyme preparation comprising a core comprising adigestive enzyme. Determination of whether a subject is in need oftreatment with an effective amount of digestive enzymes may be based ona determination that the subject has an enzyme deficiency.

In one aspect of the present disclosure, it is well known thatdetermining a dosage regimen of the compound is well within the purviewof those in the art. By way of example, the dose levels may range from100 milligrams to 10 grams as determined by weight. Further activity ofthe enzymes may range from 100 units of activity to 1,500,000 units ofactivity per dose for amylases, lipases and proteases, respectively.

In another embodiment, the disclosure relates to methods of treatmentcomprising administering to a subject with a neurological orneuropsychiatric condition susceptible to treatment with digestiveenzymes, at least two doses of a composition comprising atherapeutically effective amount of the coated digestive enzymepreparations. In certain embodiments, about 80% of the enzyme isreleased by about 30 minutes in a dissolution test performed at pH 6.0.In other embodiments, about 80% of the enzyme is released by about 30minutes after the coated digestive enzyme preparations reach the smallintestine.

The disclosure further relates in another aspect to the delivery ofdigestive enzymes with improved safety of administration. The lipid coatadds weight to the enzyme preparation, which reduces the potential foraerosolization. Previous uncoated enzymes have been shown to becomeaerosolized, and can therefore be inhaled and contact the nasal cavityor the lungs, causing injury to the mucosa of those taking and thoseadministering the enzyme preparation.

The disclosure further relates to the improvement of administering asachet preparation for delivery to children. The disclosure specificallyrelates to the administration of a coated or uncoated digestive enzymepreparation, housed in a sachet which allows for particular types ofadministration including but not limited to administration in food,drink, or direct administration into the oral cavity or directly intothe GI system through a NG-tube, G-tube or other GI entrances. The useof a sachet delivery of enzymes has heretofore not been utilized in theenzyme preparations presently marketed. In one embodiment, the sachetrepresents a single unit dosage or multiple doses for a day. The sachetof a trilaminar pouch allows the enzyme or enzyme/lipid powder to remainstable, and allows for ease of administration.

The disclosure further relates to the administering of the coated oruncoated enzyme preparation in a sachet or pouch preparation for ease ofdelivery to children and adults. In some embodiments, the disclosurespecifically relates to the administration of a coated or uncoatedenzyme particle preparation, housed in a sachet or pouch. Thisfacilitates administration, including but not limited to, administrationin food or drink, direct administration into the oral cavity, oradministration directly into the GI system through an NG-tube, G-tube orother GI entrances or deliveries.

Compositions comprising an effective amount of the compound may beadministered via any conventional route including but not limited tooral, parenteral, intramuscular, intravenous, transmucosal, transdermal,suppository or other method. Further the oral administration can be inthe form of pellets, capsules, caplets, beadlets, sprinkles, tablets,softgels or other carrier.

The pharmaceutical formulations can also be prepared for parenteral use.Such formulations typically take the form of sterile isotonic solutionsof the active ingredient according to standard pharmaceutical practice.

In one embodiment of the present disclosure, the increase of proteindigestion of an individual suffering from a neuropsychiatric disorderleads to the improvement of such disorders. In another embodiment, anindividual suffering from or diagnosed with a neuropsychiatric disorderbenefits from the administration of digestive enzymes since digestiveenzymes aid in the protein digestion process. In one embodiment, theneuropsychiatric symptoms of an individual suffering from or diagnosedwith the neuropsychiatric disorder is improved or alleviated from theadministration of digestive enzymes.

The present invention provides a method for using digestive enzymes andtheir derivatives to alleviate the symptoms of neuropsychiatricdisorders. The method comprises administering to the individual adigestive enzyme either naturally or recombinantly derived, or theirderivatives, in an amount effective to reduce the symptoms of theneuropsychiatric disorder.

Provided herein are methods of preventing one or more symptomsassociated with a neuropsychiatric disorder by administering acomposition described herein. As used herein, “prevention” refers toprophylaxis, prevention of onset of symptoms, prevention of progressionof a neuropsychiatric disorder. As used herein, “inhibition”,“prevention”, “treatment” and “treating” refer to, for example, stasisof symptoms, as well as partial or full amelioration of one or moresymptoms associated with a neuropsychiatric disorder. The compositionsdescribed herein may be used to minimize the developmental disruptionassociated with schizophrenia. Patients may be assessed with respect tothe prodromal (pre-onset) phase of the illness, which can be detected upto 30 months before the onset of symptoms. Administration of thecompositions may be used to limit or reduce the number of patients whogo on to develop schizophrenia, experience transient or self-limitingpsychotic symptoms and the non-specific symptoms of social withdrawal,irritability, dysphoria, and clumsiness during the prodromal phase.

Compositions can be administered to a patient in an amount that iseffective for producing some desired therapeutic effect by alleviatingone or more symptoms associated with a neuropsychiatric disorder at areasonable benefit/risk ratio applicable to any medical treatment. Atherapeutically effective amount is an amount achieves at leastpartially a desired therapeutic or prophylactic effect in tissuesubject. The amount of digestive enzymes necessary to bring aboutalleviation one or more symptoms associated with a neuropsychiatricdisorder is not fixed per se. The amount of digestive enzymesadministered may vary with the type of disorder, extensiveness of thedisorder, and size of the patient suffering from the disorder. Aresponse is achieved when the patient experiences partial or totalalleviation, or reduction of one or more signs or symptoms of illness.The patient's symptoms can remain static (i.e., not get worse) or can bereduced.

A physician can readily determine and prescribe the effective amount(ED50) of the composition required. For example, the physician couldstart doses of the compounds employed in the composition at levels lowerthan that required in order to achieve the desired therapeutic effectand gradually increase the dosage until the desired effect is achieved.Alternatively, a dose can remain constant.

In such methods of treatment, one or more symptoms are ameliorated orreduced following administration of a composition provided herein. Inone embodiment, one or more symptoms of such disorders are reduced inseverity or duration by about 2%, about 5%, about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about90%, about 95%, or about 100%. In another embodiment, one or moresymptoms of such disorders are reduced in severity or duration by about2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold,about 50-fold, about 55-fold, about 60-fold, about 65-fold, about70-fold, about 75-fold, about 80-fold, about 90-fold, about 95-fold,about 100-fold or more.

The DSM IV Diagnostic Criteria for Schizophrenia may be used to assesswhether administration of a composition described herein reduces theseverity and/or duration of one or more symptoms of schizophrenia.

In one embodiment, one or more characteristic symptoms are reduced inseverity and/or duration following administration of a compositiondescribed herein. For example, two (or more) of the following, eachpresent for less than half or less than a quarter of a 1-month period(or less if successfully treated): delusions, hallucinations,disorganized speech (e.g., frequent derailment or incoherence), grosslydisorganized or catatonic behavior, negative symptoms, i.e., affectiveflattening, alogia, or avolition.

In another embodiment, signs of social/occupational dysfunction areimproved following administration of a composition described herein.That is, a patient may exhibit an improvement in one or more major areasof functioning such as work, interpersonal relations, or self-care.

In yet another embodiment, the duration of symptoms may be reduced inseverity and/or duration following administration of a compositiondescribed herein. That is, continuous signs of disturbance that meetCriterion A may persist for less than 6 months, 5 months, 4 months, 3months, 2 months, 1 month, 3 weeks, 2 weeks or 1 week.

Another aspect provided herein is combination therapy of a patient witha composition described herein along with another therapeuticallyeffective agent or rehabilitation.

In one embodiment, the one or more agents are an antipsychoticmedication. Exemplary antipsychotic medications are dopamine antagonistsand serotonin antagonists.

Examples of dopamine antagonists include, but are not limited to:acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride,butaclamol, clomipramine (mild), chlorpromazine, chlorprothixene,clopenthixol, clozapine, domperidone, droperidol, eticlopride,flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide,loxapine, mesoridazine, levomepromazine, metoclopramide, nafadotride,nemonapride, olanzapine, penfluridol, perazine, perphenazine, pimozide,prochlorperazine, promazine, quetiapine, raclopride, remoxipride,risperidone, piperone, spiroxatrine, stepholidine, sulpiride,sultopride, tetrahydropalmatine, thiethylperazine, thioridazine,thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine,and ziprasidone.

Examples of serotonin antagonists include, but are not limited to: 5-HT3antagonists, 5-HT2A receptor antagonists (e.g., ketanserin, which 5HT2A,5 HT2C and alpha 1 receptors).

In another embodiment, therapeutically effective rehabilitationincludes, but is not limited to, psychotherapy, vocationalrehabilitation, social rehabilitation, or a combination thereof.

In another embodiment of the disclosure a transgenic mouse as describedby Ratty et. al. (U.S. Pat. No. 5,723,719) and incorporated herein byreference, is utilized to examine the efficacy of the digestive enzymepreparation with respect to administration of an effective amount of theenzyme and evaluating the enzyme's effect on the circling phenotype ofthe transgenic mouse.

The application of these enzymes of the high protease classification asapplied to the chakragati mouse represents a novel discovery for the useof enzymes for neuropsychiatric disorders.

In one embodiment, the digestive enzyme has an effect on the circlingbehavior and thus on neuropsychiatric disorders including suchconditions as schizophrenia.

Studies with mouse models can effectively identify molecules orcompounds which may effectively change behaviors in humans. The scale-upof such findings in mice is part of the traditional drug developmentpathway.

The chakragati (ckr) mouse, the result of a transgenic insertionalmutation, exhibits an abnormal circling behavior in response toenvironmental stress cues, such as cage banging. Wild-type littermatesand those that were heterozygous for the transgene insertion did notexhibit this circling phenotype. Analysis of the ckr mouse genomeindicates genetic rearrangements on mouse chromosome 16. A US Patent wasgranted for the chakragati mouse (U.S. Pat. No. 5,723,719).

Since its discovery, extensive genetic, pharmacological and behavioralresearch has been carried out on the ckr mouse. The research undertakenpoints to the utility of the ckr mouse as a screening tool forneuropsychiatric drug discovery. Cerca Insights Sdn Bhd has developed acascade of assays, the ckr screen, to characterize the properties ofnovel antipsychotic compounds. The insights generated from the ckrscreen may be used to enhance the assessment of efficacy across thepositive, negative and cognitive domains of schizophrenia.

The endophenotypes that have been reported in the literature withrespect to the ckr mouse are as follows: asymmetric up-regulation ofdopaminergic tone, circling, hyperactivity, prepulse inhibition deficit,latent inhibition (LI), social withdrawal, lateral ventricularenlargement, agenesis of the corpus callosum, and reduction ofmyelinated neurons in striatum.

The human clinical manifestations of the above mouse endophenotypes areas follows: Left hemi-spatial preference may be linked to asymmetricstriatal dopaminergic activity common to all psychoses. A subgroup ofschizophrenia patients has underlying right striatal hyper-dopaminergia.There is a greater pathological involvement of the dominant hemispherein schizophrenia and of the non-dominant hemisphere in bipolar disorder.(Lyon et al. 1992; Bracha 1989; Lohr & Caliguiri 1995).

Yet another human clinical manifestation of the above endophenotypes:Left-prone circling behavior (neglect of right-sided turning) was foundin unmedicated schizophrenic patients. A tendency was noted for circlingto occur more frequently among paranoid than nonparanoid schizophrenics.(Bracha 1987; Marder & Woods 1987).

Yet another human clinical manifestation of the above endophenotypes:hyperactivation (reduced task-related suppression) of default regionsand hyperconnectivity of the default network may contribute todisturbances of thought in schizophrenia and risk for the illness.(Whitfield-Gabrelli et al. 2009).

Yet another human clinical manifestation of the above endophenotypes:impairment in prepulse inhibition (PPI) is generally seen assensorimotor deficits. PPI disruption occurs in the prodromal stage ofschizophrenia and in patients with schizotypical personality disorder.(Quednow et al. 2009; Kumari et al. 2008; Kunugi et al. 2007).

In yet another human clinical manifestation of the above endophenotypes:there is the absence of latent inhibition (LI) in the acute phase ofschizophrenia. LI is found to be correlated to the duration of thedisease. (Rascle et al. 2001; Gray & Snowden 2005; Vaitl D et al. 2002).

In yet another human clinical manifestation of the above endophenotypes:longer duration of social withdrawal is evident in untreated disease.(Schultz et al. 2007; Iyer 2008; Hoffman 2007).

In yet another human clinical manifestation of the above endophenotypes:ventricular enlargement represents a morphometric endophenotype forschizophrenia. There is a significant correlation between the size ofthe lateral ventricles and underestimation of the metabolic activity ofthe caudate. (McDonald et al. 2006; Berkataki et al. 2006; Reig et al.2007).

In yet another human clinical manifestation of the above endophenotypes:reductions in the thickness of the anterior callosum differentiatebetween high-risk individuals who transition to psychosis and those whodo not, which is highly predictive of transition. (Walterfang et al.2008).

In yet another human clinical manifestation of the above endophenotypes:myelin impairment is a key factor in the pathogenic loop of psychiatricdiseases and drug addiction. (Feng 2008).

The chakragati (ckr) mouse has been utilized as a model forschizophrenia. Many “typical” and “atypical” antipsychotics have beentested on this mouse model prior to, and subsequent to approval inhumans.

The circling phenotype exhibits a disruption in the endogenous geneticlocus affecting motor function, and the circling behavior may representan aberration associated with nigrostriatal neurons of the brain. Thismay affect multiple pathways of neurotransmission such as dopamine,adrenaline, noradrenaline, serotonin or GABA.

The chakragati mouse is a unique and validated animal model which tests“antipsychotic” potency of novel compounds. The mice exhibit apersistent overactivity of the dopamine system caused by a selectiveincrease in striatal D₂ receptor subtypes. In general, antipsychoticmedications are thought to reduce dopamine overactivity by the followingmechanisms: 1) stimulating dopamine autoreceptors on dopamine neurons,thereby reducing functional activity of the dopamine system and 2)blocking post-synaptic dopamine receptors on dopaminoreceptive neuronsor other neurotransmitter systems secondary to dopaminoreceptiveneurons.

The chakragati (ckr) mouse has been proposed as a model of aspects ofschizophrenia. The mice, created serendipitously as a result oftransgenic insertional mutation, exhibit spontaneous circling,hyperactivity, hypertone of the dopamine system, reduced socialinteractions, enlarged lateral ventricles, deficits in pre-pulseinhibition of acoustic startle and deficits in the latent inhibition ofconditioned learning, (Dawe et al. 2010). In 2010 Dawe et al. studiedthe dose dependent effects of antipsychotic drugs (haloperidol,pimozide, risperidone, clozapine, olanzapine, ziprasidone, quetiapineand aripiprazole) on the spontaneous hyperactivity of the mice. All theantipsychotic drugs tested dose-dependently suppressed spontaneoushyperactivity. Aripiprazole, which is known to be a dopamine D₂ receptorpartial agonist, exhibited a tri-phasic dose-response, initiallysuppressing hyperactivity at low doses, having little effect onhyperactivity at intermediate doses, and suppressing activity again athigh doses. These data suggest that the spontaneous circling andhyperactivity of the ckr mouse may allow screening of candidateantipsychotic compounds, distinguishing compounds with aripiprazole-likeprofiles.

Aripiprazole, (also known as ABILIFY®) is an antipsychotic of a novelclass acting as a partial and selective dopamine agonist, produced adifferent pattern of change in locomotor activity across doses. At lowerdoses (1.67-10 mg/kg) it produced an apparently dose-dependent reductionin motor activity followed by an increase in motor activity (15 mg/kg)and a subsequent suppression of motor activity (30 mg/kg). It a may bethat this multiphasic pattern of change in motor activity across dosesreflects the dopamine receptor partial agonist activity of aripiprazole.Thus, the nature of the dose-dependent response in ckr mouse would beexpected to differentiate a similar dose-dependent pattern of motordisturbance but the low level of basal activity in wild type mice wouldmake this difficult to detect. Even haloperidol, which is associatedwith far stronger extrapyramidal motor side effects than aripiprazole,did not produce a significant suppression in the locomotor activity ofcontrol mice monitored during the dark cycle when they are most active,(Neuroscience, Dawe et al. 2010).

Administration of aripiprazole dose-dependently reduced the locomotoractivity of ckr mice (F6,54_4.626, P_0.001; FIG. 6B). Post-hoc Dunnett'stest comparisons with the vehicle control revealed that doses of 3-10mg/kg significantly reduced locomotor activity. The response appeared tobe multiphasic as a higher dose of 15 mg/kg did not significantlysuppress locomotor activity while a higher still dose of 30 mg/kg againsignificantly suppressed locomotor activity. Observationally, the doseof 30 mg/kg appeared to be associated with marked overall suppression ofmotor function suggestive of severe sedation. Although it was notpossible to fit the dose response curve function to the complete dataset; it was possible to fit a subset of the data describing the initialsuppression of activity at doses from 1.67 to 10 mg/kg with a curvepredicting an ED50 of 2.695 mg/kg (FIG. 6B). However, the responsespredicted by the function fitted failed to correlate with the actualvalues observed (R2_0.811, P_0.189), (Dawe et al. 2010).

Thus ckr mice homozygous for the transgene insertion show aconstellation of anatomical, biochemical and behavioral deficits whichresemble those often reported in schizophrenic patients, as shown in thefollowing Table. (Torres et al. 2008).

Condition Schizophrenia Ckr Mice Aberrant Behaviors Circling Behavior &Hyperactivity Yes Yes Sensorimotor Gating Deficits Yes Yes BrainPathologies Ventricular Enlargement Yes Yes Myelination AbnormalitiesYes Yes Metabolic Deficits Yes Yes Response to Antipsychotics Clozapineand Olanzapine Yes Yes Neurochemical Correlates Alterations in DopamineSystems Yes Yes Deficit is in Choline and N- Yes Yes acetylaspartateTypical Age of Onset of Pathology Early Adulthood Yes Yes**Sex-Dependent Prevalence of Disease *Human and mice share importantgenomic, anatomical and physiological similarities. These similarities,particularly in the genes involved in brain development, might provideinsight into disease pathogenesis. { . . . } **(Postnatal Day 10 foronset of Aberrant Behaviors) (Torres 2008)

The validity of the ckr mouse mutant for understanding the pathogenesisof schizophrenia is further supported in its ability to respond toantipsychotic drug treatment. The most salient endophenotype in thechakragati (ckr) mouse is its circling behavior. Under conditions ofsubjective stress, the mutant mouse shows consistent circling behaviorwith individual turns from 10 to 80 full body turns per minute. Thisbehavior syndrome is also characterized by lateral circling behavior(i.e. a left-preference population bias), postural asymmetry andhyperactivity to sensory stimuli. In this context drugs that block theN-Methyl-D-Aspartate (NMDA) subtype of the glutamate receptor such asphencyclidine (PCP, also known as angel dust) and ketamine (a dissociateanesthetic), usually elicit a psychotic-like-state that resemblesschizophrenia in preclinical models of the disease. This psychotic-likestate includes aberrant behavior syndromes (i.e., positive symptoms)similar to those listed for the ckr mouse. It should be noted thatatypical neuroleptics such as clozapine and olanzapine (antipsychoticagents that selectively alleviate symptoms of schizophrenia) alsoalleviate the lateralized circling behavior and aberrant posturalasymmetry exhibited by the ckr mouse. (Torres et al. 2008).

EXAMPLES Example 1 Pancreatin

Pancreatin is a substance comprising enzymes, principally amylase,lipase, and protease, obtained from the pancreas of the hog, Sus scrofaLinné var. domesticus Gray (Fam. Suidae) or of the ox, Bos taurus Linné(Fam. Bovidae). Pancreatin contains, in each mg, not less than 25 U.S.P.units of amylase activity, not less than 2 U.S.P. units of lipaseactivity, and not less than 25 U.S.P. units of protease activity.Pancreatin of a higher digestive power may be labeled as a whole-numbermultiple of the three minimum activities or may be diluted by admixturewith lactose, or with sucrose containing not more than 3.25 percent ofstarch, or with pancreatin of lower digestive power.

Example 2 Pancrelipase

Pancrelipase is a substance containing enzymes, principally lipase, withamylase and protease, obtained from the pancreas of the hog, Sus scrofaLinné var. domesticus Gray (Fam. Suidae). It contains, in each mg, notless than 24 U.S.P. Units of lipase activity, and not less than 100U.S.P. Units of amylase activity, and not less than 100 U.S.P. Units ofprotease activity.

The drug substance, pancreatic enzyme concentrate (porcine origin) ispurchased from an appropriate supplier. The properties of an exemplarypancreatic enzyme concentrate (pancreatin) suitable for use in theproducts of this invention are described in the table below.

Parameter U.S.P. Specification Protease (U.S.P.) NLT 25 U.S.P.units/dose Lipase (U.S.P.) NLT 2 U.S.P. units/dose Amylase (U.S.P.) NLT25 U.S.P. units/dose Fat (U.S.P.) NMT 6.0%* Loss on Drying (U.S.P.) NMT5.0% Escherichia coli (U.S.P.) Neg/10 g Salmonella species (U.S.P.)Neg/10 g *If less than 75 U/mg protease, 6 U/mg lipase or 75 U/mgamylase, then specification is not more than (NMT) 3.0%

Example 3 Mouse Model Study I

Attenuation of hyperactivity in the ckr mouse has been shown to bepredictive of antipsychotic efficacy. By way of testing digestiveenzymes to determine their effect on the circling behavior andhyperactivity of the ckr transgenic mouse, two strengths of the enzymeCM100 were tested on the mouse. (FIG. 1). CM100 was administered twicedaily for 14 days.

Dosing of the ckr mouse was separated into two strengths: a 10 mgpancreatin suspended in 1 mL of water and a second dosage of 20 mg ofpancreatin suspended in 1 mL of water. (FIG. 2). The vehicle used wasautoclaved reverse osmosis water. The dosage regimen consisted of twicedaily dosing for 14 days at 0800 hours and 2000 hours. Oral gavage wasthe route of administration. A 20 G autoclavable gavage needle wasutilized, and the administration was done at 0.1 ml/10 g BW. Themethodology as described may be altered accordingly as one skilled inthe art of administration of enzymes or administration via gavagemethodology to mice. One ordinarily skilled in the art would be able toadminister the enzyme.

The instant disclosure is comprised of an enzyme preparation comprisedof amylases, proteases and lipases. Doses used had a human equivalentstrength of between 155,000 and 310,000 units of protease activity, themain component of the enzyme preparation. (FIG. 3).

Dosing of the ckr mouse commenced day 1 and continued to day 14. Dosingwas conducted twice daily for 14 days, once in the morning between 7 amand 8 am and once in the evening between 7 pm and 8 pm (12 hours apart).The open field assays were conducted on 6 days: day 1, day 3, day 7, day14, day 15 and day 18. Distance moved was recorded in 10 min-bins duringthe 20 minutes monitoring period. Results were compared to the data forthe same parameters for 10 minutes determined for untreated ckr mice inprior experiments (n=54).

For the 20 mg/ml (high dose), one-way ANOVA showed significant changesin distance moved, (F6,87=3.1713, p=0.0076). Paired t-test showedsignificant differences in velocity between untreated/D1 (t=1.98969,p=0.0011)*, untreated/D3 (t=1.98969, p=0.0454)**, untreated/D7,(t=1.98969, p=0.0157)** and untreated/D18, (t=1.98969, p=0.0203)**.Tukey-Kramer test showed significance between untreated/D1 with p<0.05.

2-way ANOVA showed significant differences in distance moved between lowand high dose subjects across time (F1,14=5.3582, p=0.0363). Within thesubjects of high and low dose, there are significant differences acrosstime (F5,10=4.4951, p=0.0209).

For 20 mg/ml (high dose), one-way ANOVA showed significant changes invelocity (F6,87=3.1984, p=0.0072). Paired t-test showed significantdifferences in velocity between untreated/D1 (t=1.98969, p=0.0009)*,untreated/D3 (t=1.98969, p=0.0399)**, untreated/D7, (t=1.98969,p=0.0211)** and untreated/D18, (t=1.98969, p=0.0201)**.

Example 4 Mouse Model Study II

Dosing of the ckr mouse was separated into two strengths: a 10 mgpancreatin suspended in 1 mL of water and a second dosage of 20 mg ofpancreatin suspended in 1 mL of water. (FIG. 2). The vehicle used wasautoclaved reverse osmosis water. The dosage regimen consisted of twicedaily dosing for 14 days at 0800 hours and 2000 hours. Oral gavage wasthe route of administration. A 20 G autoclavable gavage needle wasutilized, and the administration was done at 0.1 ml/10 g BW. Themethodology as described may be altered accordingly as one skilled inthe art of administration of enzymes or administration via gavagemethodology to mice. One ordinarily skilled in the art would be able toadminister the enzyme.

The instant disclosure is comprised of an enzyme preparation comprisedof amylases, proteases and lipases. Doses used had a human equivalentstrength of between 155,000 and 310,000 units of protease activity, themain component of the enzyme preparation. (FIG. 3).

Dosing commenced day 1 and continued to day 14. Dosing was conductedtwice daily for 14 days, once in the morning between 7 am and 8 am andonce in the evening between 7 pm and 8 pm (12 hours apart). The openfield assays were conducted on 6 days: day 1, day 3, day 7, day 14, day15 and day 18. Velocity was recorded in 10 min-bins during the 20 minutemonitoring period. These were compared to the data for the sameparameters for 10 minutes determined for untreated ckr mice in priorexperiments (n=54).

For 20 mg/ml (high dose), one-way ANOVA showed significant changes invelocity (F6,87=3.1984, p=0.0072). Paired t-test showed significantdifferences in velocity between untreated/D1 (t=1.98969, p=0.0009)*,untreated/D3 (t=1.98969, p=0.0399)**, untreated/D7, (t=1.98969,p=0.0211)** and untreated/D18, (t=1.98969, p=0.0201).

Tukey-Kramer test showed significance between untreated/D1 with p<0.05.

2-way ANOVA showed significant differences in velocity between low andhigh dose subjects across time (F1,14=5.0932, p=0.0405). Within thesubjects of high and low dose, there are significant differences acrosstime (F5,10=4.6769, p=0.0184).

Example 5 Mouse Model Study III

Amphetamine-induced hyperactivity as a model of psychosis inschizophrenia is well established in the industry. FIGS. 7 and 8 are twographs that depict the results of administration of CM-182 at 30 mg/ml(i.e., approximately 465,000 units of protease) to mice injected withamphetamine to induce hyperactivity and to mice injected with saline asa control.

The dose significantly attenuated the amphetamine-induced hyperactivity,noted as an insignificant difference between the two groups of mice intotal distance moved in FIG. 7 and in velocity in FIG. 8. It was alsoobserved that CM-182 did not affect baseline activity in these mice,suggesting that the attenuation of hyperactivity occurred in a mannerunrelated to sedation. Essentially, the administered compound isnon-sedating. What the present inventors have identified is thatsignificance exists between the two of the groups in both graphs (butnot in the 30 mg/ml group), suggesting that the amphetamine did indeedinduce hyperactivity to begin with.

While preferred embodiments have been shown and described herein, suchembodiments are provided by way of example only. Numerous variations,changes and substitutions may occur without departing from thedisclosure. It should be understood that various alternatives to theembodiments of the disclosure described herein may be employed inpracticing the disclosure. It is intended that the following claimsdefine the scope of the disclosure and that methods and structureswithin the scope of these claims and their equivalents be coveredthereby.

What is claimed is:
 1. A method for preventing or treating a patientexhibiting one or more symptoms of a neuropsychiatric disordercomprising administering a therapeutically effective amount of acomposition comprising digestive enzymes to the individual, wherein oneor more symptoms of said neuropsychiatric disorder are treated.
 2. Themethod of claim 1, wherein the neuropsychiatric disorder is aschizophreniform disorder or a mild anxiety state.
 3. The method ofclaim 2, wherein said schizophreniform disorder is schizophrenia orpsychosis.
 4. A method for preventing or treating one or more symptomsof schizophrenia or psychosis in a patient administering atherapeutically effective amount of a composition comprising digestiveenzymes to the individual, wherein said one or more symptoms ofschizophrenia or psychosis are treated.
 5. The method of claim 1,wherein the one or more symptoms are selected from the group consistingof one or more positive symptoms, one or more negative symptoms, one ormore symptoms of cognitive impairment, and a combination thereof.
 6. Themethod of claim 4, wherein the one or more symptoms are selected fromthe group consisting of one or more positive symptoms, one or morenegative symptoms, one or more symptoms of cognitive impairment, and acombination thereof.
 7. The method of any one of claims 1 to 6, whereinsaid one or more symptoms are reduced in severity or duration by about2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about100%.
 8. The method of claim 7 wherein said composition is administereduntil one or more symptoms are partially or completely reduced.
 9. Themethod of claim 7, wherein said composition is administered 1, 2, 3 or 4times a day until one or more symptoms are partially or completelyreduced.
 10. The method of claim 7, wherein said composition isadministered 1, 2, 3 or 4 times a week until one or more symptoms arepartially or completely reduced.
 11. The method of claim 7, wherein saidmethod further comprises administering one or more additional agents.12. The method of claim 11, wherein said one or more agents is anantipsychotic medication.
 13. The method of claim 12, wherein saidantipsychotic medication is a dopamine antagonist or a serotoninantagonist.
 14. The method of any one of claims 7, wherein said methodfurther comprises psychotherapy, vocational rehabilitation, socialrehabilitation, or a combination thereof.
 15. The method of claims 5 or6, wherein the one or more positive symptoms comprise hallucinations,delusions, disorganized thought, disorganized speech, movementdisorders, bizarre behavior, or a combination thereof.
 16. The method ofclaims 5 or 6, wherein the one or more negative symptoms comprise lossof motivation, restricted range of emotional experience and expression,reduced hedonic capacity, affective flattening, alogia, avolition, or acombination thereof.
 17. The method of claims 5 or 6, wherein the one ormore symptoms of cognitive impairment comprise poor executive function,inability to use learned information, difficulty paying attention and/orfocusing, or a combination thereof.
 18. The method of claims 1 or 4,wherein the composition comprising digestive enzymes comprises amylases,lipases, proteases, or a combination thereof.
 19. The method of claim18, wherein the composition further comprises chymotrypsin, trypsin,pancreatin, papain, or a combination thereof.
 20. The method of claim18, wherein the digestive enzymes are derived from a source selectedfrom the group consisting of animal enzymes, plant enzymes, syntheticenzymes, and a combination thereof.
 21. The method of claim 20, whereinthe animal enzyme is derived from a mammal.
 22. The method of claim 21,wherein the mammal is a pig.
 23. The method of claim 20, wherein theanimal enzyme is derived from a pancreas.
 24. The method of claims 1 or4, wherein the compositions comprising digestive enzymes aremanufactured using a technology selected from the group consisting ofenteric coating, lipid encapsulation, direct compression, drygranulation, wet granulation, and a combination thereof.
 25. The methodof claim 24, wherein the composition is administered orally.
 26. Themethod of claim 24, wherein said composition is a dosage formulationselected from the group consisting of pills, tablets, capsules,microcapsules, mini-capsules, time released capsules, mini-tabs,sprinkles, and a combination thereof.
 27. The method of claim 18,wherein the total amount of protease in said composition is from about10,000 to about 1,500,000 U.S.P. units/dose.
 28. The method of claim 27,wherein the total amount of protease in said composition is about 5,000;about 7,500; about 10,000; about 15,000; about 20,000; about 25,000;about 30,000; about 40,000; about 50,000; about 65,000; about 75,000;about 100,000; about 140,000; about 140,400; about 150,000; about200,000; about 250,000; about 300,000; about 350,000; about 400,000;about 450,000; about 465,000; about 500,000; about 550,000; about600,000; about 650,000; about 700,000; about 750,000; about 800,000;about 850,000; about 900,000; about 950,000; about 1,000,000; about1,050,000; about 1,100,000; about 1,150,000; about 1,200,000; about1,250,000; about 1,300,000; about 1,350,000; about 1,400,000; about1,450,000; or about 1,500,000; about 1,200,000; about 1,250,000; about1,300,000; about 1,350,000; about 1,400,000; about 1,450,000; or about1,500,000 U.S.P. units/dose.
 29. The method of claim 18, wherein thetotal amount of amylase in said composition is from about 1,000 to about15,000,000 U.S.P. units/dose.
 30. The method of claim 29, wherein thetotal amount of amylase in said composition is about 1,000; about 3,000;about 5,000; about 7,500; about 10,000; about 15,000; about 20,000;about 25,000; about 30,000; about 40,000; about 50,000; about 65,000;about 75,000; about 100,000; about 144,000; about 500,000; about1,000,000; about 2,000,000; about 3,000,000; about 4,000,000; about5,000,000; about 6,000,000; about 7,000,000; about 8,000,000; about9,000,000; about 10,000,000; about 11,000,000; about 12,000,000; about13,000,000; about 14,000,000; and about 15,000,000 U.S.P. units/dose.31. The method of claim 18, wherein the total amount of lipase in saidcomposition is from about 1,500 to about 282,000 U.S.P. units/dose. 32.The method of claim 31, wherein the total amount of lipase in saidcomposition is about 1,500; about 1,880; about 2,000; about 3,000; about5,000; about 7,500; about 10,000; about 15,000; about 20,000; about23,000; about 23,040; about 25,000; about 30,000; about 40,000; about50,000; about 65,000; about 75,000; about 100,000; about 125,000; about150,000; about 200,000; about 250,000; and about 282,000 U.S.P.units/dose.
 33. A composition comprising digestive enzymes for use inthe prevention or treatment of one or more symptoms of aneuropsychiatric disorder.
 34. The composition of claim 33, wherein theneuropsychiatric disorder is a schizophreniform disorder or a mildanxiety state.
 35. The composition of claim 34, wherein saidschizophreniform disorder is schizophrenia or psychosis.
 36. Acomposition comprising digestive enzymes for use in the prevention ortreatment of one or more symptoms of schizophrenia or psychosis.
 37. Thecomposition of claims 33 or 36, wherein the one or more symptoms areselected from the group consisting of one or more positive symptoms, oneor more negative symptoms, one or more symptoms of cognitive impairment,and a combination thereof.
 38. The composition of claim 37, wherein theone or more positive symptoms comprise hallucinations, delusions,disorganized thought, disorganized speech, movement disorders, bizarrebehavior, or a combination thereof.
 39. The composition of claim 37,wherein the one or more negative symptoms comprise loss of motivation,restricted range of emotional experience and expression, reduced hedoniccapacity, affective flattening, alogia, avolition, or a combinationthereof.
 40. The composition of claim 37, wherein the one or moresymptoms of cognitive impairment are comprise poor executive function,inability to use learned information, difficulty paying attention and/orfocusing, or a combination thereof.
 41. The composition of claims 33 or36, wherein the composition comprising digestive enzymes comprisesamylases, lipases, proteases, or a combination thereof.
 42. Thecomposition of claim 41, wherein the composition further compriseschymotrypsin, trypsin, pancreatin, papain, and a combination thereof.43. The composition of claims 33 or 36, wherein the digestive enzymesare derived from a source selected from the group consisting of animalenzymes, plant enzymes, synthetic enzymes, and a combination thereof.44. The composition of claim 43, wherein the animal enzyme is derivedfrom a mammal.
 45. The composition of claim 44, wherein the mammal is apig.
 46. The composition of claim 43, wherein the animal enzyme isderived from a pancreas.
 47. The composition of claims 33 or 36, whereinthe compositions comprising digestive enzymes are manufactured using atechnology selected from the group consisting of enteric coating, lipidencapsulation, direct compression, dry granulation, wet granulation, anda combination thereof.
 48. The composition of claim 47, wherein thecomposition is formulated for oral administration.
 49. The compositionof claim 47, wherein said composition is a dosage formulation selectedfrom the group consisting of pills, tablets, capsules, microcapsules,mini-capsules, time released capsules, mini-tabs, sprinkles, and acombination thereof.
 50. The composition of claim 41, wherein the totalamount of protease in said composition is from about 10,000 to about1,500,000 U.S.P. units/dose.
 51. The composition of claim 50, whereinthe total amount of protease in said composition is about 5,000; about7,500; about 10,000; about 15,000; about 20,000; about 25,000; about30,000; about 40,000; about 50,000; about 65,000; about 75,000; about100,000; about 140,000; about 140,400; about 150,000; about 200,000;about 250,000; about 300,000; about 350,000; about 400,000; about450,000; about 465,000; about 500,000; about 550,000; about 600,000;about 650,000; about 700,000; about 750,000; about 800,000; about850,000; about 900,000; about 950,000; about 1,000,000; about 1,050,000;about 1,100,000; about 1,150,000; about 1,200,000; about 1,250,000;about 1,300,000; about 1,350,000; about 1,400,000; about 1,450,000; orabout 1,500,000; about 1,200,000; about 1,250,000; about 1,300,000;about 1,350,000; about 1,400,000; about 1,450,000; or about 1,500,000U.S.P. units/dose.
 52. The composition of claim 41, wherein the totalamount of amylase in said composition is from about 1,000 to about15,000,000 U.S.P. units/dose.
 53. The composition of claim 52, whereinthe total amount of amylase in said composition is about 1,000; about3,000; about 5,000; about 7,500; about 10,000; about 15,000; about20,000; about 25,000; about 30,000; about 40,000; about 50,000; about65,000; about 75,000; about 100,000; about 144,000; about 500,000; about1,000,000; about 2,000,000; about 3,000,000; about 4,000,000; about5,000,000; about 6,000,000; about 7,000,000; about 8,000,000; about9,000,000; about 10,000,000; about 11,000,000; about 12,000,000; about13,000,000; about 14,000,000; and about 15,000,000 U.S.P. units/dose.54. The composition of claim 41, wherein the total amount of lipase insaid composition is from about 1,500 to about 282,000 U.S.P. units/dose.55. The composition of claim 54, wherein the total amount of lipase insaid composition is about 1,500; about 1,880; about 2,000; about 3,000;about 5,000; about 7,500; about 10,000; about 15,000; about 20,000;about 20,000; about 23,000; about 23,040; about 25,000; about 25,000;about 30,000; about 40,000; about 50,000; about 65,000; about 75,000;about 100,000; about 125,000; about 150,000; about 200,000; about250,000; and about 282,000 U.S.P. units/dose.
 56. Use of a compositionof any one of claims 33-55 in the formulation of a medicament for thetreatment of one or more symptoms of a neuropsychiatric disorder. 57.The use of claim 56, wherein the neuropsychiatric disorder is aschizophreniform disorder or a mild anxiety state.
 58. The use of claim57, wherein said schizophreniform disorder is schizophrenia orpsychosis.
 59. The use of claim 56, wherein the one or more symptoms areselected from the group consisting of one or more positive symptoms, oneor more negative symptoms, one or more symptoms of cognitive impairment,and a combination thereof.
 60. The use of claim 59, wherein the one ormore positive comprise hallucinations, delusions, disorganized thought,disorganized speech, movement disorders, bizarre behavior, or acombination thereof.
 61. The use of claim 59, wherein the one or morenegative symptoms comprise loss of motivation, restricted range ofemotional experience and expression, reduced hedonic capacity, affectiveflattening, alogia, avolition, or a combination thereof.
 62. The use ofclaim 59, wherein the one or more symptoms of cognitive impairmentcomprise poor executive function, inability to use learned information,difficulty paying attention and/or focusing, or a combination thereof.63. The use of claim 56, wherein the composition comprising digestiveenzymes comprises amylases, lipases, proteases, or a combinationthereof.
 64. The use of claim 63, wherein the composition furthercomprises chymotrypsin, trypsin, pancreatin, papain, and a combinationthereof.
 65. The use of claim 56, wherein the digestive enzymes arederived from a source selected from the group consisting of animalenzymes, plant enzymes, synthetic enzymes, and a combination thereof.66. The use of claim 65, wherein the animal enzyme is derived from amammal.
 67. The use of claim 66, wherein the mammal is a pig.
 68. Theuse of claim 65 wherein the animal enzyme is derived from a pancreas.69. The use of claim 56, wherein the compositions comprising digestiveenzymes are manufactured using a technology selected from the groupconsisting of enteric coating, lipid encapsulation, direct compression,dry granulation, wet granulation, and a combination thereof.
 70. The useof claim 69, wherein the composition is formulated for oraladministration.
 71. The use of claim 69, wherein said composition is adosage formulation selected from the group consisting of pills, tablets,capsules, microcapsules, mini-capsules, time released capsules,mini-tabs, sprinkles, and a combination thereof.
 72. The use of claim63, wherein the total amount of protease in said composition is fromabout 10,000 to about 1,500,000 U.S.P. units/dose.
 73. The use of claim72, wherein the total amount of protease in said composition is about5,000; about 7,500; about 10,000; about 15,000; about 20,000; about25,000; about 30,000; about 40,000; about 50,000; about 65,000; about75,000; about 100,000; about 140,000; about 140,400; about 150,000;about 200,000; about 250,000; about 300,000; about 350,000; about400,000; about 450,000; about 465,000; about 500,000; about 550,000;about 600,000; about 650,000; about 700,000; about 750,000; about800,000; about 850,000; about 900,000; about 950,000; about 1,000,000;about 1,050,000; about 1,100,000; about 1,150,000; about 1,200,000;about 1,250,000; about 1,300,000; about 1,350,000; about 1,400,000;about 1,450,000; or about 1,500,000; about 1,200,000; about 1,250,000;about 1,300,000; about 1,350,000; about 1,400,000; about 1,450,000; orabout 1,500,000 U.S.P. units/dose.
 74. The use of claim 63, wherein thetotal amount of amylase in said composition is from about 1,000 to about15,000,000 U.S.P. units/dose.
 75. The use of claim 74, wherein the totalamount of amylase in said composition is about 1,000; about 3,000; about5,000; about 7,500; about 10,000; about 15,000; about 20,000; about25,000; about 30,000; about 40,000; about 50,000; about 65,000; about75,000; about 100,000; about 144,000; about 500,000; about 1,000,000;about 2,000,000; about 3,000,000; about 4,000,000; about 5,000,000;about 6,000,000; about 7,000,000; about 8,000,000; about 9,000,000;about 10,000,000; about 11,000,000; about 12,000,000; about 13,000,000;about 14,000,000; and about 15,000,000 U.S.P. units/dose.
 76. The use ofclaim 63, wherein the total amount of lipase in said composition is fromabout 1,500 to about 282,000 U.S.P. units/dose.
 77. The use of claim 76,wherein the total amount of lipase in said composition is about 1,500;about 1,880; about 2,000; about 3,000; about 5,000; about 7,500; about10,000; about 15,000; about 20,000; about 20,000; about 23,000; about23,040; about 25,000; about 25,000; about 30,000; about 40,000; about50,000; about 65,000; about 75,000; about 100,000; about 125,000; about150,000; about 200,000; about 250,000; and about 282,000 U.S.P.units/dose.
 78. The use of claim 56, wherein said one or more symptomsare reduced in severity or duration by about 2%, about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 90%, about 95%, or about 100%.
 79. Use of a compositionof any one of claims 33-55 in the formulation of a medicament for thetreatment of one or more symptoms of schizophrenia or psychosis.
 80. Theuse of claim 79, wherein the one or more symptoms are selected from thegroup consisting of one or more positive symptoms, one or more negativesymptoms, one or more symptoms of cognitive impairment, and acombination thereof.
 81. The use of claim 80, wherein the one or morepositive comprise hallucinations, delusions, disorganized thought,disorganized speech, movement disorders, bizarre behavior, or acombination thereof.
 82. The use of claim 80, wherein the one or morenegative symptoms comprise loss of motivation, restricted range ofemotional experience and expression, reduced hedonic capacity, affectiveflattening, alogia, avolition, or a combination thereof.
 83. The use ofclaim 80, wherein the one or more symptoms of cognitive impairmentcomprise poor executive function, inability to use learned information,difficulty paying attention and/or focusing, or a combination thereof.84. The use of claim 79, wherein the composition comprising digestiveenzymes comprises amylases, lipases, proteases, or a combinationthereof.
 85. The use of claim 84, wherein the composition furthercomprises chymotrypsin, trypsin, pancreatin, papain, and a combinationthereof.
 86. The use of claim 79, wherein the digestive enzymes arederived from a source selected from the group consisting of animalenzymes, plant enzymes, synthetic enzymes, and a combination thereof.87. The use of claim 86, wherein the animal enzyme is derived from amammal.
 88. The use of claim 87, wherein the mammal is a pig.
 89. Theuse of claim 86, wherein the animal enzyme is derived from a pancreas.90. The use of claim 79, wherein the compositions comprising digestiveenzymes are manufactured using a technology selected from the groupconsisting of enteric coating, lipid encapsulation, direct compression,dry granulation, wet granulation, and a combination thereof.
 91. The useof claim 90, wherein the composition is administered orally.
 92. The useof claim 90, wherein said composition is a dosage formulation selectedfrom the group consisting of pills, tablets, capsules, microcapsules,mini-capsules, time released capsules, mini-tabs, sprinkles, and acombination thereof.
 93. The use of claim 84, wherein the total amountof protease in said composition is from about 10,000 to about 1,500,000U.S.P. units/dose.
 94. The use of claim 93, wherein the total amount ofprotease in said composition is about 5,000; about 7,500; about 10,000;about 15,000; about 20,000; about 25,000; about 30,000; about 40,000;about 50,000; about 65,000; about 75,000; about 100,000; about 140,000;about 140,400; about 150,000; about 200,000; about 250,000; about300,000; about 350,000; about 400,000; about 450,000; about 465,000;about 500,000; about 550,000; about 600,000; about 650,000; about700,000; about 750,000; about 800,000; about 850,000; about 900,000;about 950,000; about 1,000,000; about 1,050,000; about 1,100,000; about1,150,000; about 1,200,000; about 1,250,000; about 1,300,000; about1,350,000; about 1,400,000; about 1,450,000; or about 1,500,000; about1,200,000; about 1,250,000; about 1,300,000; about 1,350,000; about1,400,000; about 1,450,000; or about 1,500,000 U.S.P. units/dose. 95.The use of claim 84, wherein the total amount of amylase in saidcomposition is from about 1,000 to about 15,000,000 U.S.P. units/dose.96. The use of claim 95, wherein the total amount of amylase in saidcomposition is about 1,000; about 3,000; about 5,000; about 7,500; about10,000; about 15,000; about 20,000; about 25,000; about 30,000; about40,000; about 50,000; about 65,000; about 75,000; about 100,000; about144,000; about 500,000; about 1,000,000; about 2,000,000; about3,000,000; about 4,000,000; about 5,000,000; about 6,000,000; about7,000,000; about 8,000,000; about 9,000,000; about 10,000,000; about11,000,000; about 12,000,000; about 13,000,000; about 14,000,000; andabout 15,000,000 U.S.P. units/dose.
 97. The use of claim 84, wherein thetotal amount of lipase in said composition is from about 1,500 to about282,000 U.S.P. units/dose.
 98. The use of claim 97, wherein the totalamount of lipase in said composition is about 1,500; about 1,880; about2,000; about 3,000; about 5,000; about 7,500; about 10,000; about15,000; about 20,000; about 20,000; about 23,000; about 23,040; about25,000; about 25,000; about 30,000; about 40,000; about 50,000; about65,000; about 75,000; about 100,000; about 125,000; about 150,000; about200,000; about 250,000; and about 282,000 U.S.P. units/dose.
 99. The useof claim 79, wherein said one or more symptoms are reduced in severityor duration by about 2%, about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%,about 95%, or about 100%.